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Sample records for models signal human

  1. A computational model of human auditory signal processing and perception

    DEFF Research Database (Denmark)

    Jepsen, Morten Løve; Ewert, Stephan D.; Dau, Torsten

    2008-01-01

    A model of computational auditory signal-processing and perception that accounts for various aspects of simultaneous and nonsimultaneous masking in human listeners is presented. The model is based on the modulation filterbank model described by Dau et al. [J. Acoust. Soc. Am. 102, 2892 (1997...... discrimination with pure tones and broadband noise, tone-in-noise detection, spectral masking with narrow-band signals and maskers, forward masking with tone signals and tone or noise maskers, and amplitude-modulation detection with narrow- and wideband noise carriers. The model can account for most of the key...... properties of the data and is more powerful than the original model. The model might be useful as a front end in technical applications....

  2. Human circadian phase estimation from signals collected in ambulatory conditions using an autoregressive model

    NARCIS (Netherlands)

    Gil, Enrique A; Aubert, Xavier L; Møst, Els I S; Beersma, Domien G M

    Phase estimation of the human circadian rhythm is a topic that has been explored using various modeling approaches. The current models range from physiological to mathematical, all attempting to estimate the circadian phase from different physiological or behavioral signals. Here, we have focused on

  3. A Review on Human Body Communication: Signal Propagation Model, Communication Performance, and Experimental Issues

    Directory of Open Access Journals (Sweden)

    Jian Feng Zhao

    2017-01-01

    Full Text Available Human body communication (HBC, which uses the human body tissue as the transmission medium to transmit health informatics, serves as a promising physical layer solution for the body area network (BAN. The human centric nature of HBC offers an innovative method to transfer the healthcare data, whose transmission requires low interference and reliable data link. Therefore, the deployment of HBC system obtaining good communication performance is required. In this regard, a tutorial review on the important issues related to HBC data transmission such as signal propagation model, channel characteristics, communication performance, and experimental considerations is conducted. In this work, the development of HBC and its first attempts are firstly reviewed. Then a survey on the signal propagation models is introduced. Based on these models, the channel characteristics are summarized; the communication performance and selection of transmission parameters are also investigated. Moreover, the experimental issues, such as electrodes and grounding strategies, are also discussed. Finally, the recommended future studies are provided.

  4. Human-like motion planning model for driving in signalized intersections

    Directory of Open Access Journals (Sweden)

    Yanlei Gu

    2017-10-01

    Full Text Available Highly automated and fully autonomous vehicles are much more likely to be accepted if they react in the same way as human drivers do, especially in a hybrid traffic situation, which allows autonomous vehicles and human-driven vehicles to share the same road. This paper proposes a human-like motion planning model to represent how human drivers assess environments and operate vehicles in signalized intersections. The developed model consists of a pedestrian intention detection model, gap detection model, and vehicle control model. These three submodels are individually responsible for situation assessment, decision making, and action, and also depend on each other in the process of motion planning. In addition, these submodels are constructed and learned on the basis of human drivers' data collected from real traffic environments. To verify the effectiveness of the proposed motion planning model, we compared the proposed model with actual human driver and pedestrian data. The experimental results showed that our proposed model and actual human driver behaviors are highly similar with respect to gap acceptance in intersections.

  5. Explaining neural signals in human visual cortex with an associative learning model.

    Science.gov (United States)

    Jiang, Jiefeng; Schmajuk, Nestor; Egner, Tobias

    2012-08-01

    "Predictive coding" models posit a key role for associative learning in visual cognition, viewing perceptual inference as a process of matching (learned) top-down predictions (or expectations) against bottom-up sensory evidence. At the neural level, these models propose that each region along the visual processing hierarchy entails one set of processing units encoding predictions of bottom-up input, and another set computing mismatches (prediction error or surprise) between predictions and evidence. This contrasts with traditional views of visual neurons operating purely as bottom-up feature detectors. In support of the predictive coding hypothesis, a recent human neuroimaging study (Egner, Monti, & Summerfield, 2010) showed that neural population responses to expected and unexpected face and house stimuli in the "fusiform face area" (FFA) could be well-described as a summation of hypothetical face-expectation and -surprise signals, but not by feature detector responses. Here, we used computer simulations to test whether these imaging data could be formally explained within the broader framework of a mathematical neural network model of associative learning (Schmajuk, Gray, & Lam, 1996). Results show that FFA responses could be fit very closely by model variables coding for conditional predictions (and their violations) of stimuli that unconditionally activate the FFA. These data document that neural population signals in the ventral visual stream that deviate from classic feature detection responses can formally be explained by associative prediction and surprise signals.

  6. Blue-light filtering alters angiogenic signaling in human retinal pigmented epithelial cells culture model.

    Science.gov (United States)

    Vila, Natalia; Siblini, Aya; Esposito, Evangelina; Bravo-Filho, Vasco; Zoroquiain, Pablo; Aldrees, Sultan; Logan, Patrick; Arias, Lluis; Burnier, Miguel N

    2017-11-02

    Light exposure and more specifically the spectrum of blue light contribute to the oxidative stress in Age-related macular degeneration (AMD). The purpose of the study was to establish whether blue light filtering could modify proangiogenic signaling produced by retinal pigmented epithelial (RPE) cells under different conditions simulating risk factors for AMD. Three experiments were carried out in order to expose ARPE-19 cells to white light for 48 h with and without blue light-blocking filters (BLF) in different conditions. In each experiment one group was exposed to light with no BLF protection, a second group was exposed to light with BLF protection, and a control group was not exposed to light. The ARPE-19 cells used in each experiment prior to light exposure were cultured for 24 h as follows: Experiment 1) Normoxia, Experiment 2) Hypoxia, and Experiment 3) Lutein supplemented media in normoxia. The media of all groups was harvested after light exposure for sandwich ELISA-based assays to quantify 10 pro-angiogenic cytokines. A significant decrease in angiogenin secretion levels and a significant increase in bFGF were observed following light exposure, compared to dark conditions, in both normoxia and hypoxia conditions. With the addition of a blue light-blocking filter in normoxia, a significant increase in angiogenin levels was observed. Although statistical significance was not achieved, blue light filters reduce light-induced secretion of bFGF and VEGF to near normal levels. This trend is also observed when ARPE-19 cells are grown under hypoxic conditions and when pre-treated with lutein prior to exposure to experimental conditions. Following light exposure, there is a decrease in angiogenin secretion by ARPE-19 cells, which was abrogated with a blue light - blocking filter. Our findings support the position that blue light filtering affects the secretion of angiogenic factors by retinal pigmented epithelial cells under normoxic, hypoxic, and lutein

  7. Signaling hierarchy regulating human endothelial cell development.

    Science.gov (United States)

    Kelly, Melissa A; Hirschi, Karen K

    2009-05-01

    Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these studies. Using human embryonic stem cells as a model system, we were able to reproducibly and robustly generate differentiated endothelial cells via coculture on OP9 marrow stromal cells. We found that, in contrast to studies in the mouse, bFGF and VEGF had no specific effects on the initiation of human vasculogenesis. However, exogenous Ihh promoted endothelial cell differentiation, as evidenced by increased production of cells with cobblestone morphology that coexpress multiple endothelial-specific genes and proteins, form lumens, and exhibit DiI-AcLDL uptake. Inhibition of BMP signaling using Noggin or BMP4, specifically, using neutralizing antibodies suppressed endothelial cell formation; whereas, addition of rhBMP4 to cells treated with the hedgehog inhibitor cyclopamine rescued endothelial cell development. Our studies revealed that Ihh promoted human endothelial cell differentiation from pluripotent hES cells via BMP signaling, providing novel insights applicable to modulating human endothelial cell formation and vascular regeneration for human clinical therapies.

  8. 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...

  9. Spatio-temporal Model of Endogenous ROS and Raft-Dependent WNT/Beta-Catenin Signaling Driving Cell Fate Commitment in Human Neural Progenitor Cells

    Science.gov (United States)

    Haack, Fiete; Lemcke, Heiko; Ewald, Roland; Rharass, Tareck; Uhrmacher, Adelinde M.

    2015-01-01

    Canonical WNT/β-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/β-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear β-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of β-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/β-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream β-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/β-catenin signal or as amplifier during continuous auto-/parcrine WNT/β-catenin signaling. In addition we provide the first stochastic computational model of WNT/β-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent β-catenin activation. The model’s predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the

  10. Modeling binaural signal detection

    NARCIS (Netherlands)

    Breebaart, D.J.

    2001-01-01

    With the advent of multimedia technology and powerful signal processing systems, audio processing and reproduction has gained renewed interest. Examples of products that have been developed are audio coding algorithms to efficiently store and transmit music and speech, or audio reproduction systems

  11. Mathematical Modelling Plant Signalling Networks

    KAUST Repository

    Muraro, D.; Byrne, H.M.; King, J.R.; Bennett, M.J.

    2013-01-01

    methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This mathematical analysis of sub-cellular molecular mechanisms paves the way for more

  12. Models of calcium signalling

    CERN Document Server

    Dupont, Geneviève; Kirk, Vivien; Sneyd, James

    2016-01-01

    This book discusses the ways in which mathematical, computational, and modelling methods can be used to help understand the dynamics of intracellular calcium. The concentration of free intracellular calcium is vital for controlling a wide range of cellular processes, and is thus of great physiological importance. However, because of the complex ways in which the calcium concentration varies, it is also of great mathematical interest.This book presents the general modelling theory as well as a large number of specific case examples, to show how mathematical modelling can interact with experimental approaches, in an interdisciplinary and multifaceted approach to the study of an important physiological control mechanism. Geneviève Dupont is FNRS Research Director at the Unit of Theoretical Chronobiology of the Université Libre de Bruxelles;Martin Falcke is head of the Mathematical Cell Physiology group at the Max Delbrück Center for Molecular Medicine, Berlin;Vivien Kirk is an Associate Professor in the Depar...

  13. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  14. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    International Nuclear Information System (INIS)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C.; Ballestas, Mary E.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  15. The ultimate intrinsic signal-to-noise ratio of loop- and dipole-like current patterns in a realistic human head model.

    Science.gov (United States)

    Pfrommer, Andreas; Henning, Anke

    2018-03-13

    The ultimate intrinsic signal-to-noise ratio (UISNR) represents an upper bound for the achievable SNR of any receive coil. To reach this threshold a complete basis set of equivalent surface currents is required. This study systematically investigated to what extent either loop- or dipole-like current patterns are able to reach the UISNR threshold in a realistic human head model between 1.5 T and 11.7 T. Based on this analysis, we derived guidelines for coil designers to choose the best array element at a given field strength. Moreover, we present ideal current patterns yielding the UISNR in a realistic body model. We distributed generic current patterns on a cylindrical and helmet-shaped surface around a realistic human head model. We excited electromagnetic fields in the human head by using eigenfunctions of the spherical and cylindrical Helmholtz operator. The electromagnetic field problem was solved by a fast volume integral equation solver. At 7 T and above, adding curl-free current patterns to divergence-free current patterns substantially increased the SNR in the human head (locally >20%). This was true for the helmet-shaped and the cylindrical surface. On the cylindrical surface, dipole-like current patterns had high SNR performance in central regions at ultra-high field strength. The UISNR increased superlinearly with B0 in most parts of the cerebrum but only sublinearly in the periphery of the human head. The combination of loop and dipole elements could enhance the SNR performance in the human head at ultra-high field strength. © 2018 International Society for Magnetic Resonance in Medicine.

  16. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  17. Mathematical Modelling Plant Signalling Networks

    KAUST Repository

    Muraro, D.

    2013-01-01

    During the last two decades, molecular genetic studies and the completion of the sequencing of the Arabidopsis thaliana genome have increased knowledge of hormonal regulation in plants. These signal transduction pathways act in concert through gene regulatory and signalling networks whose main components have begun to be elucidated. Our understanding of the resulting cellular processes is hindered by the complex, and sometimes counter-intuitive, dynamics of the networks, which may be interconnected through feedback controls and cross-regulation. Mathematical modelling provides a valuable tool to investigate such dynamics and to perform in silico experiments that may not be easily carried out in a laboratory. In this article, we firstly review general methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This mathematical analysis of sub-cellular molecular mechanisms paves the way for more comprehensive modelling studies of hormonal transport and signalling in a multi-scale setting. © EDP Sciences, 2013.

  18. Diabetes: Models, Signals and control

    Science.gov (United States)

    Cobelli, C.

    2010-07-01

    Diabetes and its complications impose significant economic consequences on individuals, families, health systems, and countries. The control of diabetes is an interdisciplinary endeavor, which includes significant components of modeling, signal processing and control. Models: first, I will discuss the minimal (coarse) models which describe the key components of the system functionality and are capable of measuring crucial processes of glucose metabolism and insulin control in health and diabetes; then, the maximal (fine-grain) models which include comprehensively all available knowledge about system functionality and are capable to simulate the glucose-insulin system in diabetes, thus making it possible to create simulation scenarios whereby cost effective experiments can be conducted in silico to assess the efficacy of various treatment strategies - in particular I will focus on the first in silico simulation model accepted by FDA as a substitute to animal trials in the quest for optimal diabetes control. Signals: I will review metabolic monitoring, with a particular emphasis on the new continuous glucose sensors, on the crucial role of models to enhance the interpretation of their time-series signals, and on the opportunities that they present for automation of diabetes control. Control: I will review control strategies that have been successfully employed in vivo or in silico, presenting a promise for the development of a future artificial pancreas and, in particular, I will discuss a modular architecture for building closed-loop control systems, including insulin delivery and patient safety supervision layers.

  19. Signaling hierarchy regulating human endothelial cell development

    Science.gov (United States)

    Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these stud...

  20. Lysophosphatidic Acid (LPA Signaling in Human and Ruminant Reproductive Tract

    Directory of Open Access Journals (Sweden)

    Izabela Wocławek-Potocka

    2014-01-01

    Full Text Available Lysophosphatidic acid (LPA through activating its G protein-coupled receptors (LPAR 1–6 exerts diverse cellular effects that in turn influence several physiological processes including reproductive function of the female. Studies in various species of animals and also in humans have identified important roles for the receptor-mediated LPA signaling in multiple aspects of human and animal reproductive tract function. These aspects range from ovarian and uterine function, estrous cycle regulation, early embryo development, embryo implantation, decidualization to pregnancy maintenance and parturition. LPA signaling can also have pathological consequences, influencing aspects of endometriosis and reproductive tissue associated tumors. The review describes recent progress in LPA signaling research relevant to human and ruminant reproduction, pointing at the cow as a relevant model to study LPA influence on the human reproductive performance.

  1. Astrocyte calcium signal and gliotransmission in human brain tissue.

    Science.gov (United States)

    Navarrete, Marta; Perea, Gertrudis; Maglio, Laura; Pastor, Jesús; García de Sola, Rafael; Araque, Alfonso

    2013-05-01

    Brain function is recognized to rely on neuronal activity and signaling processes between neurons, whereas astrocytes are generally considered to play supportive roles for proper neuronal function. However, accumulating evidence indicates that astrocytes sense and control neuronal and synaptic activity, indicating that neuron and astrocytes reciprocally communicate. While this evidence has been obtained in experimental animal models, whether this bidirectional signaling between astrocytes and neurons occurs in human brain remains unknown. We have investigated the existence of astrocyte-neuron communication in human brain tissue, using electrophysiological and Ca(2+) imaging techniques in slices of the cortex and hippocampus obtained from biopsies from epileptic patients. Cortical and hippocampal human astrocytes displayed spontaneous Ca(2+) elevations that were independent of neuronal activity. Local application of transmitter receptor agonists or nerve electrical stimulation transiently elevated Ca(2+) in astrocytes, indicating that human astrocytes detect synaptic activity and respond to synaptically released neurotransmitters, suggesting the existence of neuron-to-astrocyte communication in human brain tissue. Electrophysiological recordings in neurons revealed the presence of slow inward currents (SICs) mediated by NMDA receptor activation. The frequency of SICs increased after local application of ATP that elevated astrocyte Ca(2+). Therefore, human astrocytes are able to release the gliotransmitter glutamate, which affect neuronal excitability through activation of NMDA receptors in neurons. These results reveal the existence of reciprocal signaling between neurons and astrocytes in human brain tissue, indicating that astrocytes are relevant in human neurophysiology and are involved in human brain function.

  2. Human Capital Augmentation versus the Signaling Value of MBA Education

    Science.gov (United States)

    Hussey, Andrew

    2012-01-01

    Panel data on MBA graduates is used in an attempt to empirically distinguish between human capital and signaling models of education. The existence of employment observations prior to MBA enrollment allows for the control of unobserved ability or selection into MBA programs (through the use of individual fixed effects). In addition, variation in…

  3. In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

    Directory of Open Access Journals (Sweden)

    Kohei Yamamizu

    2017-03-01

    Full Text Available The blood-brain barrier (BBB is composed of four cell populations, brain endothelial cells (BECs, pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A and efflux transporters (ABCA1, BCRP, PGP, MRP5, and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

  4. RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.

    Science.gov (United States)

    Fang, Bingliang

    2016-01-01

    Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology

  5. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model.

    Science.gov (United States)

    Kurundkar, Deepali; Srivastava, Ritesh K; Chaudhary, Sandeep C; Ballestas, Mary E; Kopelovich, Levy; Elmets, Craig A; Athar, Mohammad

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Effects of human fatigue on speech signals

    Science.gov (United States)

    Stamoulis, Catherine

    2004-05-01

    Cognitive performance may be significantly affected by fatigue. In the case of critical personnel, such as pilots, monitoring human fatigue is essential to ensure safety and success of a given operation. One of the modalities that may be used for this purpose is speech, which is sensitive to respiratory changes and increased muscle tension of vocal cords, induced by fatigue. Age, gender, vocal tract length, physical and emotional state may significantly alter speech intensity, duration, rhythm, and spectral characteristics. In addition to changes in speech rhythm, fatigue may also affect the quality of speech, such as articulation. In a noisy environment, detecting fatigue-related changes in speech signals, particularly subtle changes at the onset of fatigue, may be difficult. Therefore, in a performance-monitoring system, speech parameters which are significantly affected by fatigue need to be identified and extracted from input signals. For this purpose, a series of experiments was performed under slowly varying cognitive load conditions and at different times of the day. The results of the data analysis are presented here.

  7. Polycystins, calcium signaling, and human diseases

    International Nuclear Information System (INIS)

    Delmas, Patrick; Padilla, Francoise; Osorio, Nancy; Coste, Bertrand; Raoux, Matthieu; Crest, Marcel

    2004-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major, inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of fluid-filled cysts from the tubules and collecting ducts of affected kidneys. The pathogenesis of cyst formation is currently thought to involve increased proliferation of epithelial cells, mild dedifferentiation, and fluid accumulation. In the past decade, study of ADPKD led to the discovery of a unique family of highly complex proteins, the polycystins. Loss-of-function mutations in either of two polycystin proteins, polycystin-1 or polycystin-2, give rise to ADPKD. These proteins are thought to function together as part of a multiprotein complex that may initiate Ca 2+ signals, directing attention to the regulation of intracellular Ca 2+ as a possible misstep that participates in cyst formation. Here we review what is known about the Ca 2+ signaling functions of polycystin proteins and focus on findings that have significantly advanced our physiological insight. Special attention is paid to the recently discovered role of these proteins in the mechanotransduction of the renal primary cilium and the model it suggests

  8. Modeling High-Dimensional Multichannel Brain Signals

    KAUST Repository

    Hu, Lechuan; Fortin, Norbert J.; Ombao, Hernando

    2017-01-01

    aspects: first, there are major statistical and computational challenges for modeling and analyzing high-dimensional multichannel brain signals; second, there is no set of universally agreed measures for characterizing connectivity. To model multichannel

  9. EMD-Based Symbolic Dynamic Analysis for the Recognition of Human and Nonhuman Pyroelectric Infrared Signals

    Directory of Open Access Journals (Sweden)

    Jiaduo Zhao

    2016-01-01

    Full Text Available In this paper, we propose an effective human and nonhuman pyroelectric infrared (PIR signal recognition method to reduce PIR detector false alarms. First, using the mathematical model of the PIR detector, we analyze the physical characteristics of the human and nonhuman PIR signals; second, based on the analysis results, we propose an empirical mode decomposition (EMD-based symbolic dynamic analysis method for the recognition of human and nonhuman PIR signals. In the proposed method, first, we extract the detailed features of a PIR signal into five symbol sequences using an EMD-based symbolization method, then, we generate five feature descriptors for each PIR signal through constructing five probabilistic finite state automata with the symbol sequences. Finally, we use a weighted voting classification strategy to classify the PIR signals with their feature descriptors. Comparative experiments show that the proposed method can effectively classify the human and nonhuman PIR signals and reduce PIR detector’s false alarms.

  10. EMD-Based Symbolic Dynamic Analysis for the Recognition of Human and Nonhuman Pyroelectric Infrared Signals.

    Science.gov (United States)

    Zhao, Jiaduo; Gong, Weiguo; Tang, Yuzhen; Li, Weihong

    2016-01-20

    In this paper, we propose an effective human and nonhuman pyroelectric infrared (PIR) signal recognition method to reduce PIR detector false alarms. First, using the mathematical model of the PIR detector, we analyze the physical characteristics of the human and nonhuman PIR signals; second, based on the analysis results, we propose an empirical mode decomposition (EMD)-based symbolic dynamic analysis method for the recognition of human and nonhuman PIR signals. In the proposed method, first, we extract the detailed features of a PIR signal into five symbol sequences using an EMD-based symbolization method, then, we generate five feature descriptors for each PIR signal through constructing five probabilistic finite state automata with the symbol sequences. Finally, we use a weighted voting classification strategy to classify the PIR signals with their feature descriptors. Comparative experiments show that the proposed method can effectively classify the human and nonhuman PIR signals and reduce PIR detector's false alarms.

  11. Discrete dynamic modeling of cellular signaling networks.

    Science.gov (United States)

    Albert, Réka; Wang, Rui-Sheng

    2009-01-01

    Understanding signal transduction in cellular systems is a central issue in systems biology. Numerous experiments from different laboratories generate an abundance of individual components and causal interactions mediating environmental and developmental signals. However, for many signal transduction systems there is insufficient information on the overall structure and the molecular mechanisms involved in the signaling network. Moreover, lack of kinetic and temporal information makes it difficult to construct quantitative models of signal transduction pathways. Discrete dynamic modeling, combined with network analysis, provides an effective way to integrate fragmentary knowledge of regulatory interactions into a predictive mathematical model which is able to describe the time evolution of the system without the requirement for kinetic parameters. This chapter introduces the fundamental concepts of discrete dynamic modeling, particularly focusing on Boolean dynamic models. We describe this method step-by-step in the context of cellular signaling networks. Several variants of Boolean dynamic models including threshold Boolean networks and piecewise linear systems are also covered, followed by two examples of successful application of discrete dynamic modeling in cell biology.

  12. Regression models of reactor diagnostic signals

    International Nuclear Information System (INIS)

    Vavrin, J.

    1989-01-01

    The application is described of an autoregression model as the simplest regression model of diagnostic signals in experimental analysis of diagnostic systems, in in-service monitoring of normal and anomalous conditions and their diagnostics. The method of diagnostics is described using a regression type diagnostic data base and regression spectral diagnostics. The diagnostics is described of neutron noise signals from anomalous modes in the experimental fuel assembly of a reactor. (author)

  13. MASCOTTE: analytical model of eddy current signals

    International Nuclear Information System (INIS)

    Delsarte, G.; Levy, R.

    1992-01-01

    Tube examination is a major application of the eddy current technique in the nuclear and petrochemical industries. Such examination configurations being specially adapted to analytical modes, a physical model is developed on portable computers. It includes simple approximations made possible by the effective conditions of the examinations. The eddy current signal is described by an analytical formulation that takes into account the tube dimensions, the sensor conception, the physical characteristics of the defect and the examination parameters. Moreover, the model makes it possible to associate real signals and simulated signals

  14. Robust control of dielectric elastomer diaphragm actuator for human pulse signal tracking

    Science.gov (United States)

    Ye, Zhihang; Chen, Zheng; Asmatulu, Ramazan; Chan, Hoyin

    2017-08-01

    Human pulse signal tracking is an emerging technology that is needed in traditional Chinese medicine. However, soft actuation with multi-frequency tracking capability is needed for tracking human pulse signal. Dielectric elastomer (DE) is one type of soft actuating that has great potential in human pulse signal tracking. In this paper, a DE diaphragm actuator was designed and fabricated to track human pulse pressure signal. A physics-based and control-oriented model has been developed to capture the dynamic behavior of DE diaphragm actuator. Using the physical model, an H-infinity robust control was designed for the actuator to reject high-frequency sensing noises and disturbances. The robust control was then implemented in real-time to track a multi-frequency signal, which verified the tracking capability and robustness of the control system. In the human pulse signal tracking test, a human pulse signal was measured at the City University of Hong Kong and then was tracked using DE actuator at Wichita State University in the US. Experimental results have verified that the DE actuator with its robust control is capable of tracking human pulse signal.

  15. Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery

    DEFF Research Database (Denmark)

    Kiprilov, Enko N; Awan, Aashir; Desprat, Romain

    2008-01-01

    Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC d...

  16. Models of human operators

    International Nuclear Information System (INIS)

    Knee, H.E.; Schryver, J.C.

    1991-01-01

    Models of human behavior and cognition (HB and C) are necessary for understanding the total response of complex systems. Many such models have come available over the past thirty years for various applications. Unfortunately, many potential model users remain skeptical about their practicality, acceptability, and usefulness. Such hesitancy stems in part to disbelief in the ability to model complex cognitive processes, and a belief that relevant human behavior can be adequately accounted for through the use of commonsense heuristics. This paper will highlight several models of HB and C and identify existing and potential applications in attempt to dispel such notions. (author)

  17. Protein Translation and Signaling in Human Eosinophils

    Directory of Open Access Journals (Sweden)

    Stephane Esnault

    2017-09-01

    Full Text Available We have recently reported that, unlike IL-5 and GM-CSF, IL-3 induces increased translation of a subset of mRNAs. In addition, we have demonstrated that Pin1 controls the activity of mRNA binding proteins, leading to enhanced mRNA stability, GM-CSF protein production and prolonged eosinophil (EOS survival. In this review, discussion will include an overview of cap-dependent protein translation and its regulation by intracellular signaling pathways. We will address the more general process of mRNA post-transcriptional regulation, especially regarding mRNA binding proteins, which are critical effectors of protein translation. Furthermore, we will focus on (1 the roles of IL-3-driven sustained signaling on enhanced protein translation in EOS, (2 the mechanisms regulating mRNA binding proteins activity in EOS, and (3 the potential targeting of IL-3 signaling and the signaling leading to mRNA binding activity changes to identify therapeutic targets to treat EOS-associated diseases.

  18. 4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

    International Nuclear Information System (INIS)

    Lee, Hye-Rim; Choi, Kyung-Chul

    2013-01-01

    Highlights: ► Cathepsins B and D were markedly enhanced by octylphenol (OP) in MCF-7 cells. ► OP may accelerate breast cancer cell growth and cathepsins via ER-mediated signaling. ► Breast cancer cells exposed with OP to mouse model were more aggressive. ► OP can promote metastasis through the amplification of cathepsins B and D via ER-mediated signaling pathway. -- Abstract: Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48 h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10 −6 M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of

  19. Learning sparse generative models of audiovisual signals

    OpenAIRE

    Monaci, Gianluca; Sommer, Friedrich T.; Vandergheynst, Pierre

    2008-01-01

    This paper presents a novel framework to learn sparse represen- tations for audiovisual signals. An audiovisual signal is modeled as a sparse sum of audiovisual kernels. The kernels are bimodal functions made of synchronous audio and video components that can be positioned independently and arbitrarily in space and time. We design an algorithm capable of learning sets of such audiovi- sual, synchronous, shift-invariant functions by alternatingly solving a coding and a learning pr...

  20. Warning Signals for Poor Performance Improve Human-Robot Interaction

    NARCIS (Netherlands)

    van den Brule, Rik; Bijlstra, Gijsbert; Dotsch, Ron; Haselager, Pim; Wigboldus, Daniel HJ

    2016-01-01

    The present research was aimed at investigating whether human-robot interaction (HRI) can be improved by a robot’s nonverbal warning signals. Ideally, when a robot signals that it cannot guarantee good performance, people could take preventive actions to ensure the successful completion of the

  1. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

    Directory of Open Access Journals (Sweden)

    Claudia Tulotta

    2016-02-01

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

  2. Digital Human Modeling

    Science.gov (United States)

    Dischinger, H. Charles, Jr.

    2017-01-01

    The development of models to represent human characteristics and behaviors in human factors is broad and general. The term "model" can refer to any metaphor to represent any aspect of the human; it is generally used in research to mean a mathematical tool for the simulation (often in software, which makes the simulation digital) of some aspect of human performance and for the prediction of future outcomes. This section is restricted to the application of human models in physical design, e.g., in human factors engineering. This design effort is typically human interface design, and the digital models used are anthropometric. That is, they are visual models that are the physical shape of humans and that have the capabilities and constraints of humans of a selected population. They are distinct from the avatars used in the entertainment industry (movies, video games, and the like) in precisely that regard: as models, they are created through the application of data on humans, and they are used to predict human response; body stresses workspaces. DHM enable iterative evaluation of a large number of concepts and support rapid analysis, as compared with use of physical mockups. They can be used to evaluate feasibility of escape of a suited astronaut from a damaged vehicle, before launch or after an abort (England, et al., 2012). Throughout most of human spaceflight, little attention has been paid to worksite design for ground workers. As a result of repeated damage to the Space Shuttle which adversely affected flight safety, DHM analyses of ground assembly and maintenance have been developed over the last five years for the design of new flight systems (Stambolian, 2012, Dischinger and Dunn Jackson, 2014). The intent of these analyses is to assure the design supports the work of the ground crew personnel and thereby protect the launch vehicle. They help the analyst address basic human factors engineering questions: can a worker reach the task site from the work platform

  3. Patterns of flavor signals in supersymmetric models

    Energy Technology Data Exchange (ETDEWEB)

    Goto, T. [KEK National High Energy Physics, Tsukuba (Japan)]|[Kyoto Univ. (Japan). YITP; Okada, Y. [KEK National High Energy Physics, Tsukuba (Japan)]|[Graduate Univ. for Advanced Studies, Tsukuba (Japan). Dept. of Particle and Nucelar Physics; Shindou, T. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)]|[International School for Advanced Studies, Trieste (Italy); Tanaka, M. [Osaka Univ., Toyonaka (Japan). Dept. of Physics

    2007-11-15

    Quark and lepton flavor signals are studied in four supersymmetric models, namely the minimal supergravity model, the minimal supersymmetric standard model with right-handed neutrinos, SU(5) supersymmetric grand unified theory with right-handed neutrinos and the minimal supersymmetric standard model with U(2) flavor symmetry. We calculate b{yields}s(d) transition observables in B{sub d} and B{sub s} decays, taking the constraint from the B{sub s}- anti B{sub s} mixing recently observed at Tevatron into account. We also calculate lepton flavor violating processes {mu} {yields} e{gamma}, {tau} {yields} {mu}{gamma} and {tau} {yields} e{gamma} for the models with right-handed neutrinos. We investigate possibilities to distinguish the flavor structure of the supersymmetry breaking sector with use of patterns of various flavor signals which are expected to be measured in experiments such as MEG, LHCb and a future Super B Factory. (orig.)

  4. Patterns of flavor signals in supersymmetric models

    International Nuclear Information System (INIS)

    Goto, T.; Tanaka, M.

    2007-11-01

    Quark and lepton flavor signals are studied in four supersymmetric models, namely the minimal supergravity model, the minimal supersymmetric standard model with right-handed neutrinos, SU(5) supersymmetric grand unified theory with right-handed neutrinos and the minimal supersymmetric standard model with U(2) flavor symmetry. We calculate b→s(d) transition observables in B d and B s decays, taking the constraint from the B s - anti B s mixing recently observed at Tevatron into account. We also calculate lepton flavor violating processes μ → eγ, τ → μγ and τ → eγ for the models with right-handed neutrinos. We investigate possibilities to distinguish the flavor structure of the supersymmetry breaking sector with use of patterns of various flavor signals which are expected to be measured in experiments such as MEG, LHCb and a future Super B Factory. (orig.)

  5. Mathematical Models Light Up Plant Signaling

    NARCIS (Netherlands)

    Chew, Y.H.; Smith, R.W.; Jones, H.J.; Seaton, D.D.; Grima, R.; Halliday, K.J.

    2014-01-01

    Plants respond to changes in the environment by triggering a suite of regulatory networks that control and synchronize molecular signaling in different tissues, organs, and the whole plant. Molecular studies through genetic and environmental perturbations, particularly in the model plant Arabidopsis

  6. Modeling high dimensional multichannel brain signals

    KAUST Repository

    Hu, Lechuan

    2017-03-27

    In this paper, our goal is to model functional and effective (directional) connectivity in network of multichannel brain physiological signals (e.g., electroencephalograms, local field potentials). The primary challenges here are twofold: first, there are major statistical and computational difficulties for modeling and analyzing high dimensional multichannel brain signals; second, there is no set of universally-agreed measures for characterizing connectivity. To model multichannel brain signals, our approach is to fit a vector autoregressive (VAR) model with sufficiently high order so that complex lead-lag temporal dynamics between the channels can be accurately characterized. However, such a model contains a large number of parameters. Thus, we will estimate the high dimensional VAR parameter space by our proposed hybrid LASSLE method (LASSO+LSE) which is imposes regularization on the first step (to control for sparsity) and constrained least squares estimation on the second step (to improve bias and mean-squared error of the estimator). Then to characterize connectivity between channels in a brain network, we will use various measures but put an emphasis on partial directed coherence (PDC) in order to capture directional connectivity between channels. PDC is a directed frequency-specific measure that explains the extent to which the present oscillatory activity in a sender channel influences the future oscillatory activity in a specific receiver channel relative all possible receivers in the network. Using the proposed modeling approach, we have achieved some insights on learning in a rat engaged in a non-spatial memory task.

  7. Modeling High-Dimensional Multichannel Brain Signals

    KAUST Repository

    Hu, Lechuan

    2017-12-12

    Our goal is to model and measure functional and effective (directional) connectivity in multichannel brain physiological signals (e.g., electroencephalograms, local field potentials). The difficulties from analyzing these data mainly come from two aspects: first, there are major statistical and computational challenges for modeling and analyzing high-dimensional multichannel brain signals; second, there is no set of universally agreed measures for characterizing connectivity. To model multichannel brain signals, our approach is to fit a vector autoregressive (VAR) model with potentially high lag order so that complex lead-lag temporal dynamics between the channels can be captured. Estimates of the VAR model will be obtained by our proposed hybrid LASSLE (LASSO + LSE) method which combines regularization (to control for sparsity) and least squares estimation (to improve bias and mean-squared error). Then we employ some measures of connectivity but put an emphasis on partial directed coherence (PDC) which can capture the directional connectivity between channels. PDC is a frequency-specific measure that explains the extent to which the present oscillatory activity in a sender channel influences the future oscillatory activity in a specific receiver channel relative to all possible receivers in the network. The proposed modeling approach provided key insights into potential functional relationships among simultaneously recorded sites during performance of a complex memory task. Specifically, this novel method was successful in quantifying patterns of effective connectivity across electrode locations, and in capturing how these patterns varied across trial epochs and trial types.

  8. Modeling high dimensional multichannel brain signals

    KAUST Repository

    Hu, Lechuan; Fortin, Norbert; Ombao, Hernando

    2017-01-01

    In this paper, our goal is to model functional and effective (directional) connectivity in network of multichannel brain physiological signals (e.g., electroencephalograms, local field potentials). The primary challenges here are twofold: first, there are major statistical and computational difficulties for modeling and analyzing high dimensional multichannel brain signals; second, there is no set of universally-agreed measures for characterizing connectivity. To model multichannel brain signals, our approach is to fit a vector autoregressive (VAR) model with sufficiently high order so that complex lead-lag temporal dynamics between the channels can be accurately characterized. However, such a model contains a large number of parameters. Thus, we will estimate the high dimensional VAR parameter space by our proposed hybrid LASSLE method (LASSO+LSE) which is imposes regularization on the first step (to control for sparsity) and constrained least squares estimation on the second step (to improve bias and mean-squared error of the estimator). Then to characterize connectivity between channels in a brain network, we will use various measures but put an emphasis on partial directed coherence (PDC) in order to capture directional connectivity between channels. PDC is a directed frequency-specific measure that explains the extent to which the present oscillatory activity in a sender channel influences the future oscillatory activity in a specific receiver channel relative all possible receivers in the network. Using the proposed modeling approach, we have achieved some insights on learning in a rat engaged in a non-spatial memory task.

  9. Humanized mouse models: Application to human diseases.

    Science.gov (United States)

    Ito, Ryoji; Takahashi, Takeshi; Ito, Mamoru

    2018-05-01

    Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. © 2017 Wiley Periodicals, Inc.

  10. Acquiring neural signals for developing a perception and cognition model

    Science.gov (United States)

    Li, Wei; Li, Yunyi; Chen, Genshe; Shen, Dan; Blasch, Erik; Pham, Khanh; Lynch, Robert

    2012-06-01

    The understanding of how humans process information, determine salience, and combine seemingly unrelated information is essential to automated processing of large amounts of information that is partially relevant, or of unknown relevance. Recent neurological science research in human perception, and in information science regarding contextbased modeling, provides us with a theoretical basis for using a bottom-up approach for automating the management of large amounts of information in ways directly useful for human operators. However, integration of human intelligence into a game theoretic framework for dynamic and adaptive decision support needs a perception and cognition model. For the purpose of cognitive modeling, we present a brain-computer-interface (BCI) based humanoid robot system to acquire brainwaves during human mental activities of imagining a humanoid robot-walking behavior. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model. The BCI system consists of a data acquisition unit with an electroencephalograph (EEG), a humanoid robot, and a charge couple CCD camera. An EEG electrode cup acquires brainwaves from the skin surface on scalp. The humanoid robot has 20 degrees of freedom (DOFs); 12 DOFs located on hips, knees, and ankles for humanoid robot walking, 6 DOFs on shoulders and arms for arms motion, and 2 DOFs for head yaw and pitch motion. The CCD camera takes video clips of the human subject's hand postures to identify mental activities that are correlated to the robot-walking behaviors. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model.

  11. Model for neural signaling leap statistics

    International Nuclear Information System (INIS)

    Chevrollier, Martine; Oria, Marcos

    2011-01-01

    We present a simple model for neural signaling leaps in the brain considering only the thermodynamic (Nernst) potential in neuron cells and brain temperature. We numerically simulated connections between arbitrarily localized neurons and analyzed the frequency distribution of the distances reached. We observed qualitative change between Normal statistics (with T 37.5 0 C, awaken regime) and Levy statistics (T = 35.5 0 C, sleeping period), characterized by rare events of long range connections.

  12. Model for neural signaling leap statistics

    Science.gov (United States)

    Chevrollier, Martine; Oriá, Marcos

    2011-03-01

    We present a simple model for neural signaling leaps in the brain considering only the thermodynamic (Nernst) potential in neuron cells and brain temperature. We numerically simulated connections between arbitrarily localized neurons and analyzed the frequency distribution of the distances reached. We observed qualitative change between Normal statistics (with T = 37.5°C, awaken regime) and Lévy statistics (T = 35.5°C, sleeping period), characterized by rare events of long range connections.

  13. Model for neural signaling leap statistics

    Energy Technology Data Exchange (ETDEWEB)

    Chevrollier, Martine; Oria, Marcos, E-mail: oria@otica.ufpb.br [Laboratorio de Fisica Atomica e Lasers Departamento de Fisica, Universidade Federal da ParaIba Caixa Postal 5086 58051-900 Joao Pessoa, Paraiba (Brazil)

    2011-03-01

    We present a simple model for neural signaling leaps in the brain considering only the thermodynamic (Nernst) potential in neuron cells and brain temperature. We numerically simulated connections between arbitrarily localized neurons and analyzed the frequency distribution of the distances reached. We observed qualitative change between Normal statistics (with T 37.5{sup 0}C, awaken regime) and Levy statistics (T = 35.5{sup 0}C, sleeping period), characterized by rare events of long range connections.

  14. Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries.

    Directory of Open Access Journals (Sweden)

    Sonya Hui

    Full Text Available We recently identified sphingosine-1-phosphate (S1P signaling and the cystic fibrosis transmembrane conductance regulator (CFTR as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i express critical S1P signaling elements, (ii constrict in response to S1P and (iii lose myogenic responsiveness following S1P receptor antagonism (JTE013. However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.

  15. Logic integer programming models for signaling networks.

    Science.gov (United States)

    Haus, Utz-Uwe; Niermann, Kathrin; Truemper, Klaus; Weismantel, Robert

    2009-05-01

    We propose a static and a dynamic approach to model biological signaling networks, and show how each can be used to answer relevant biological questions. For this, we use the two different mathematical tools of Propositional Logic and Integer Programming. The power of discrete mathematics for handling qualitative as well as quantitative data has so far not been exploited in molecular biology, which is mostly driven by experimental research, relying on first-order or statistical models. The arising logic statements and integer programs are analyzed and can be solved with standard software. For a restricted class of problems the logic models reduce to a polynomial-time solvable satisfiability algorithm. Additionally, a more dynamic model enables enumeration of possible time resolutions in poly-logarithmic time. Computational experiments are included.

  16. Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case?control epidemiological observations

    OpenAIRE

    Ingram, Nicola; Northwood, Emma L.; Perry, Sarah L.; Marston, Gemma; Snowden, Helen; Taylor, John C.; Scott, Nigel; Bishop, D. Timothy; Coletta, P. Louise; Hull, Mark A.

    2013-01-01

    We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case-control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4Rα (-) (/-) , IL-13 (-/-) and 'double-knockout' (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) ...

  17. Human modeling in nuclear engineering

    International Nuclear Information System (INIS)

    Yoshikawa, Hidekazu; Furuta, Kazuo.

    1994-01-01

    Review on progress of research and development on human modeling methods is made from the viewpoint of its importance on total man-machine system reliability surrounding nuclear power plant operation. Basic notions on three different approaches of human modeling (behavioristics, cognitives and sociologistics) are firstly introduced, followed by the explanation of fundamental scheme to understand human cognitives at man-machine interface and the mechanisms of human error and its classification. Then, general methodologies on human cognitive model by AI are explained with the brief summary of various R and D activities now prevailing in the human modeling communities around the world. A new method of dealing with group human reliability is also introduced which is based on sociologistic mathematical model. Lastly, problems on human model validation are discussed, followed by the introduction of new experimental method to estimate human cognitive state by psycho-physiological measurement, which is a new methodology plausible for human model validation. (author)

  18. AR Signaling in Human Malignancies: Prostate Cancer and Beyond.

    Science.gov (United States)

    Antonarakis, Emmanuel S

    2018-01-18

    The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is the role of AR signaling in other human malignancies. This special issue of Cancers initially reviews the role of AR in advanced prostate cancer, and then explores the potential importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and they also outline the interaction between AR and other cellular pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors, Wnt signaling, and epigenetic regulation in prostate cancer. The next several articles review the possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer, and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen therapies in these non-prostatic malignancies.

  19. Animal and human models to understand ageing.

    Science.gov (United States)

    Lees, Hayley; Walters, Hannah; Cox, Lynne S

    2016-11-01

    Human ageing is the gradual decline in organ and tissue function with increasing chronological time, leading eventually to loss of function and death. To study the processes involved over research-relevant timescales requires the use of accessible model systems that share significant similarities with humans. In this review, we assess the usefulness of various models, including unicellular yeasts, invertebrate worms and flies, mice and primates including humans, and highlight the benefits and possible drawbacks of each model system in its ability to illuminate human ageing mechanisms. We describe the strong evolutionary conservation of molecular pathways that govern cell responses to extracellular and intracellular signals and which are strongly implicated in ageing. Such pathways centre around insulin-like growth factor signalling and integration of stress and nutritional signals through mTOR kinase. The process of cellular senescence is evaluated as a possible underlying cause for many of the frailties and diseases of human ageing. Also considered is ageing arising from systemic changes that cannot be modelled in lower organisms and instead require studies either in small mammals or in primates. We also touch briefly on novel therapeutic options arising from a better understanding of the biology of ageing. Copyright © 2016. Published by Elsevier Ireland Ltd.

  20. Modeling Human Leukemia Immunotherapy in Humanized Mice

    Directory of Open Access Journals (Sweden)

    Jinxing Xia

    2016-08-01

    Full Text Available The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL, which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI, a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.

  1. Bipolar cell gap junctions serve major signaling pathways in the human retina.

    Science.gov (United States)

    Kántor, Orsolya; Varga, Alexandra; Nitschke, Roland; Naumann, Angela; Énzsöly, Anna; Lukáts, Ákos; Szabó, Arnold; Németh, János; Völgyi, Béla

    2017-08-01

    Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina.

  2. Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF-α and TGF-β1/ERK1/2 signaling pathways

    Science.gov (United States)

    Zhang, Changyi; Zhou, Guichi; Chen, Yezeng; Liu, Sizheng; Chen, Fen; Xie, Lichun; Wang, Wei; Zhang, Yonggang; Wang, Tianyou; Lai, Xiulan; Ma, Lian

    2018-01-01

    Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord-derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin-induced rat model of DCM. Male Lewis rats (aged 8-weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1×106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle-injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF-α, extracellular-signal regulated kinase 1/2 (ERK1/2) and TGF-β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF-α and the TGF-β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM. PMID:29115435

  3. Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models.

    Science.gov (United States)

    Della Corte, Carminia Maria; Ciaramella, Vincenza; Cardone, Claudia; La Monica, Silvia; Alfieri, Roberta; Petronini, Pier Giorgio; Malapelle, Umberto; Vigliar, Elena; Pepe, Francesco; Troncone, Giancarlo; Castellone, Maria Domenica; Troiani, Teresa; Martinelli, Erika; Ciardiello, Fortunato; Morgillo, Floriana

    2018-03-08

    Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models. We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments. The addition of selumetinib or cetuximab to osimertinib in second-line therapy reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50% to 80%, and a median progression-free survival (mPFS) of first- plus second-line of therapy of 28 weeks. The early use of combinations in first-line therapy increased the RR to 90%, with an mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0.005) as compared to osimertinib, achieving in first-line therapy an mPFS time of 17 to 18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found Hedgehog pathway activation and we showed that therapy with an SMO inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells. We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  4. Human vocal attractiveness as signaled by body size projection.

    Directory of Open Access Journals (Sweden)

    Yi Xu

    Full Text Available Voice, as a secondary sexual characteristic, is known to affect the perceived attractiveness of human individuals. But the underlying mechanism of vocal attractiveness has remained unclear. Here, we presented human listeners with acoustically altered natural sentences and fully synthetic sentences with systematically manipulated pitch, formants and voice quality based on a principle of body size projection reported for animal calls and emotional human vocal expressions. The results show that male listeners preferred a female voice that signals a small body size, with relatively high pitch, wide formant dispersion and breathy voice, while female listeners preferred a male voice that signals a large body size with low pitch and narrow formant dispersion. Interestingly, however, male vocal attractiveness was also enhanced by breathiness, which presumably softened the aggressiveness associated with a large body size. These results, together with the additional finding that the same vocal dimensions also affect emotion judgment, indicate that humans still employ a vocal interaction strategy used in animal calls despite the development of complex language.

  5. Signals of historical interlocus gene conversion in human segmental duplications.

    Directory of Open Access Journals (Sweden)

    Beth L Dumont

    Full Text Available Standard methods of DNA sequence analysis assume that sequences evolve independently, yet this assumption may not be appropriate for segmental duplications that exchange variants via interlocus gene conversion (IGC. Here, we use high quality multiple sequence alignments from well-annotated segmental duplications to systematically identify IGC signals in the human reference genome. Our analysis combines two complementary methods: (i a paralog quartet method that uses DNA sequence simulations to identify a statistical excess of sites consistent with inter-paralog exchange, and (ii the alignment-based method implemented in the GENECONV program. One-quarter (25.4% of the paralog families in our analysis harbor clear IGC signals by the quartet approach. Using GENECONV, we identify 1477 gene conversion tracks that cumulatively span 1.54 Mb of the genome. Our analyses confirm the previously reported high rates of IGC in subtelomeric regions and Y-chromosome palindromes, and identify multiple novel IGC hotspots, including the pregnancy specific glycoproteins and the neuroblastoma breakpoint gene families. Although the duplication history of a paralog family is described by a single tree, we show that IGC has introduced incredible site-to-site variation in the evolutionary relationships among paralogs in the human genome. Our findings indicate that IGC has left significant footprints in patterns of sequence diversity across segmental duplications in the human genome, out-pacing the contributions of single base mutation by orders of magnitude. Collectively, the IGC signals we report comprise a catalog that will provide a critical reference for interpreting observed patterns of DNA sequence variation across duplicated genomic regions, including targets of recent adaptive evolution in humans.

  6. Characterization of NAADP-mediated calcium signaling in human spermatozoa

    Energy Technology Data Exchange (ETDEWEB)

    Sánchez-Tusie, A.A. [Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos (Mexico); Vasudevan, S.R.; Churchill, G.C. [Department of Pharmacology, University of Oxford, Oxford OX1 3QT, England (United Kingdom); Nishigaki, T. [Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos (Mexico); Treviño, C.L., E-mail: ctrevino@ibt.unam.mx [Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos (Mexico)

    2014-01-10

    Highlights: •Human sperm cells synthesize NAADP. •NAADP-AM mediates [Ca{sup 2+}]{sub i} increases in human sperm in the absence of [Ca{sup 2+}]{sub o}. •Human sperm have two acidic compartments located in the head and midpiece. -- Abstract: Ca{sup 2+} signaling in spermatozoa plays a crucial role during processes such as capacitation and release of the acrosome, but the underlying molecular mechanisms still remain unclear. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca{sup 2+}-releasing second messenger in a variety of cellular processes. The presence of a NAADP synthesizing enzyme in sea urchin sperm has been previously reported, suggesting a possible role of NAADP in sperm Ca{sup 2+} signaling. In this work we used in vitro enzyme assays to show the presence of a novel NAADP synthesizing enzyme in human sperm, and to characterize its sensitivity to Ca{sup 2+} and pH. Ca{sup 2+} fluorescence imaging studies demonstrated that the permeable form of NAADP (NAADP-AM) induces intracellular [Ca{sup 2+}] increases in human sperm even in the absence of extracellular Ca{sup 2+}. Using LysoTracker®, a fluorescent probe that selectively accumulates in acidic compartments, we identified two such stores in human sperm cells. Their acidic nature was further confirmed by the reduction in staining intensity observed upon inhibition of the endo-lysosomal proton pump with Bafilomycin, or after lysosomal bursting with glycyl-L-phenylalanine-2-naphthylamide. The selective fluorescent NAADP analog, Ned-19, stained the same subcellular regions as LysoTracker®, suggesting that these stores are the targets of NAADP action.

  7. Robust Indoor Human Activity Recognition Using Wireless Signals.

    Science.gov (United States)

    Wang, Yi; Jiang, Xinli; Cao, Rongyu; Wang, Xiyang

    2015-07-15

    Wireless signals-based activity detection and recognition technology may be complementary to the existing vision-based methods, especially under the circumstance of occlusions, viewpoint change, complex background, lighting condition change, and so on. This paper explores the properties of the channel state information (CSI) of Wi-Fi signals, and presents a robust indoor daily human activity recognition framework with only one pair of transmission points (TP) and access points (AP). First of all, some indoor human actions are selected as primitive actions forming a training set. Then, an online filtering method is designed to make actions' CSI curves smooth and allow them to contain enough pattern information. Each primitive action pattern can be segmented from the outliers of its multi-input multi-output (MIMO) signals by a proposed segmentation method. Lastly, in online activities recognition, by selecting proper features and Support Vector Machine (SVM) based multi-classification, activities constituted by primitive actions can be recognized insensitive to the locations, orientations, and speeds.

  8. A parametric framework for modelling of bioelectrical signals

    CERN Document Server

    Mughal, Yar Muhammad

    2016-01-01

    This book examines non-invasive, electrical-based methods for disease diagnosis and assessment of heart function. In particular, a formalized signal model is proposed since this offers several advantages over methods that rely on measured data alone. By using a formalized representation, the parameters of the signal model can be easily manipulated and/or modified, thus providing mechanisms that allow researchers to reproduce and control such signals. In addition, having such a formalized signal model makes it possible to develop computer tools that can be used for manipulating and understanding how signal changes result from various heart conditions, as well as for generating input signals for experimenting with and evaluating the performance of e.g. signal extraction methods. The work focuses on bioelectrical information, particularly electrical bio-impedance (EBI). Once the EBI has been measured, the corresponding signals have to be modelled for analysis. This requires a structured approach in order to move...

  9. Signal analysis of accelerometry data using gravity-based modeling

    Science.gov (United States)

    Davey, Neil P.; James, Daniel A.; Anderson, Megan E.

    2004-03-01

    Triaxial accelerometers have been used to measure human movement parameters in swimming. Interpretation of data is difficult due to interference sources including interaction of external bodies. In this investigation the authors developed a model to simulate the physical movement of the lower back. Theoretical accelerometery outputs were derived thus giving an ideal, or noiseless dataset. An experimental data collection apparatus was developed by adapting a system to the aquatic environment for investigation of swimming. Model data was compared against recorded data and showed strong correlation. Comparison of recorded and modeled data can be used to identify changes in body movement, this is especially useful when cyclic patterns are present in the activity. Strong correlations between data sets allowed development of signal processing algorithms for swimming stroke analysis using first the pure noiseless data set which were then applied to performance data. Video analysis was also used to validate study results and has shown potential to provide acceptable results.

  10. Signaling pathway networks mined from human pituitary adenoma proteomics data

    Directory of Open Access Journals (Sweden)

    Zhan Xianquan

    2010-04-01

    Full Text Available Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins, comparative proteomic data (56 differentially expressed proteins, and nitroproteomic data (17 nitroproteins. There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a

  11. Signal Processing Model for Radiation Transport

    Energy Technology Data Exchange (ETDEWEB)

    Chambers, D H

    2008-07-28

    This note describes the design of a simplified gamma ray transport model for use in designing a sequential Bayesian signal processor for low-count detection and classification. It uses a simple one-dimensional geometry to describe the emitting source, shield effects, and detector (see Fig. 1). At present, only Compton scattering and photoelectric absorption are implemented for the shield and the detector. Other effects may be incorporated in the future by revising the expressions for the probabilities of escape and absorption. Pair production would require a redesign of the simulator to incorporate photon correlation effects. The initial design incorporates the physical effects that were present in the previous event mode sequence simulator created by Alan Meyer. The main difference is that this simulator transports the rate distributions instead of single photons. Event mode sequences and other time-dependent photon flux sequences are assumed to be marked Poisson processes that are entirely described by their rate distributions. Individual realizations can be constructed from the rate distribution using a random Poisson point sequence generator.

  12. Modeling human color categorization

    NARCIS (Netherlands)

    van den Broek, Egon; Schouten, Th.E.; Kisters, P.M.F.

    A unique color space segmentation method is introduced. It is founded on features of human cognition, where 11 color categories are used in processing color. In two experiments, human subjects were asked to categorize color stimuli into these 11 color categories, which resulted in markers for a

  13. Human migraine models

    DEFF Research Database (Denmark)

    Iversen, Helle Klingenberg

    2001-01-01

    , which is a human experience. A set-up for investigations of experimental headache and migraine in humans, has been evaluated and headache mechanisms explored by using nitroglycerin and other headache-inducing agents. Nitric oxide (NO) or other parts of the NO activated cascade seems to be responsible...

  14. Tracking Human Mobility Using WiFi Signals

    DEFF Research Database (Denmark)

    Sapiezynski, Piotr; Stopczynski, Arkadiusz; Gatej, Radu

    2015-01-01

    We study six months of human mobility data, including WiFi and GPS traces recorded with high temporal resolution, and find that time series of WiFi scans contain a strong latent location signal. In fact, due to inherent stability and low entropy of human mobility, it is possible to assign location...... to WiFi access points based on a very small number of GPS samples and then use these access points as location beacons. Using just one GPS observation per day per person allows us to estimate the location of, and subsequently use, WiFi access points to account for 80% of mobility across a population....... These results reveal a great opportunity for using ubiquitous WiFi routers for high-resolution outdoor positioning, but also significant privacy implications of such side-channel location tracking....

  15. Melatonin: a chemical photoperiodic signal with clinical significance in humans.

    Science.gov (United States)

    Pang, S F; Pang, C S; Poon, A M; Lee, P P; Liu, Z M; Shiu, S Y

    1998-03-01

    Secretion of pineal melatonin exhibits a diumal rhythm and a seasonal rhythm in humans. Night-time melatonin is high at 3-5 year-old and decreases with age. Many drugs and pathological conditions also change melatonin levels in the circulation. Melatonin has a mild sedative effect and has been used effectively in synchronizing the sleep-wake cycle of patients with sleep disorders. Immunoenhancing, anti-cancer, anti-aging and anti-oxidant effects of melatonin have been proposed. Recent studies suggest that melatonin receptors are present in central and peripheral tissues. The importance of melatonin receptors on the nervous, reproductive, immune and renal functions is implicated. Studies on the molecular biology, physiology and pathology of melatonin receptors in different tissues are progressing rapidly. The physiological and pathological changes in melatonin secretion, multifarious melatonin actions, and diverse melatonin receptors reported suggest that melatonin is a photoperiodic signal with clinical significance in humans.

  16. Integrated Environmental Modelling: Human decisions, human challenges

    Science.gov (United States)

    Glynn, Pierre D.

    2015-01-01

    Integrated Environmental Modelling (IEM) is an invaluable tool for understanding the complex, dynamic ecosystems that house our natural resources and control our environments. Human behaviour affects the ways in which the science of IEM is assembled and used for meaningful societal applications. In particular, human biases and heuristics reflect adaptation and experiential learning to issues with frequent, sharply distinguished, feedbacks. Unfortunately, human behaviour is not adapted to the more diffusely experienced problems that IEM typically seeks to address. Twelve biases are identified that affect IEM (and science in general). These biases are supported by personal observations and by the findings of behavioural scientists. A process for critical analysis is proposed that addresses some human challenges of IEM and solicits explicit description of (1) represented processes and information, (2) unrepresented processes and information, and (3) accounting for, and cognizance of, potential human biases. Several other suggestions are also made that generally complement maintaining attitudes of watchful humility, open-mindedness, honesty and transparent accountability. These suggestions include (1) creating a new area of study in the behavioural biogeosciences, (2) using structured processes for engaging the modelling and stakeholder communities in IEM, and (3) using ‘red teams’ to increase resilience of IEM constructs and use.

  17. Robust Indoor Human Activity Recognition Using Wireless Signals

    Directory of Open Access Journals (Sweden)

    Yi Wang

    2015-07-01

    Full Text Available Wireless signals–based activity detection and recognition technology may be complementary to the existing vision-based methods, especially under the circumstance of occlusions, viewpoint change, complex background, lighting condition change, and so on. This paper explores the properties of the channel state information (CSI of Wi-Fi signals, and presents a robust indoor daily human activity recognition framework with only one pair of transmission points (TP and access points (AP. First of all, some indoor human actions are selected as primitive actions forming a training set. Then, an online filtering method is designed to make actions’ CSI curves smooth and allow them to contain enough pattern information. Each primitive action pattern can be segmented from the outliers of its multi-input multi-output (MIMO signals by a proposed segmentation method. Lastly, in online activities recognition, by selecting proper features and Support Vector Machine (SVM based multi-classification, activities constituted by primitive actions can be recognized insensitive to the locations, orientations, and speeds.

  18. Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth

    Science.gov (United States)

    Ono, Masanori; Yin, Ping; Navarro, Antonia; Moravek, Molly B.; Coon, John S.; Druschitz, Stacy A.; Gottardi, Cara J.; Bulun, Serdar E.

    2014-01-01

    Objective Dysregulation of WNT signaling plays a central role in tumor cell growth and progression. Our goal was to assess the effect of three WNT/β-catenin pathway inhibitors, Inhibitor of β-Catenin And TCF4 (ICAT), niclosamide, and XAV939 on the proliferation of primary cultures of human uterine leiomyoma cells. Design Prospective study of human leiomyoma cells obtained from myomectomy or hysterectomy. Setting University research laboratory. Patient(s) Women (n=38) aged 27–53 years undergoing surgery. Intervention(s) Adenoviral ICAT overexpression or treatment with varying concentrations of niclosamide or XAV939. Main Outcome Measure(s) Cell proliferation, cell death, WNT/β-catenin target gene expression or reporter gene regulation, β-catenin levels and cellular localization. Result(s) ICAT, niclosamide, or XAV939 inhibit WNT/β-catenin pathway activation and exert anti-proliferative effects in primary cultures of human leiomyoma cells. Conclusion(s) Three WNT/β-catenin pathway inhibitors specifically block human leiomyoma growth and proliferation, suggesting that the canonical WNT pathway may be a potential therapeutic target for the treatment of uterine leiomyoma. Our findings provide rationale for further preclinical and clinical evaluation of ICAT, niclosamide, and XAV939 as candidate anti-tumor agents for uterine leiomyoma. PMID:24534281

  19. Statistical Challenges in Modeling Big Brain Signals

    KAUST Repository

    Yu, Zhaoxia

    2017-11-01

    Brain signal data are inherently big: massive in amount, complex in structure, and high in dimensions. These characteristics impose great challenges for statistical inference and learning. Here we review several key challenges, discuss possible solutions, and highlight future research directions.

  20. Statistical Challenges in Modeling Big Brain Signals

    KAUST Repository

    Yu, Zhaoxia; Pluta, Dustin; Shen, Tong; Chen, Chuansheng; Xue, Gui; Ombao, Hernando

    2017-01-01

    Brain signal data are inherently big: massive in amount, complex in structure, and high in dimensions. These characteristics impose great challenges for statistical inference and learning. Here we review several key challenges, discuss possible

  1. Behavioral Signal Processing: Deriving Human Behavioral Informatics From Speech and Language

    Science.gov (United States)

    Narayanan, Shrikanth; Georgiou, Panayiotis G.

    2013-01-01

    The expression and experience of human behavior are complex and multimodal and characterized by individual and contextual heterogeneity and variability. Speech and spoken language communication cues offer an important means for measuring and modeling human behavior. Observational research and practice across a variety of domains from commerce to healthcare rely on speech- and language-based informatics for crucial assessment and diagnostic information and for planning and tracking response to an intervention. In this paper, we describe some of the opportunities as well as emerging methodologies and applications of human behavioral signal processing (BSP) technology and algorithms for quantitatively understanding and modeling typical, atypical, and distressed human behavior with a specific focus on speech- and language-based communicative, affective, and social behavior. We describe the three important BSP components of acquiring behavioral data in an ecologically valid manner across laboratory to real-world settings, extracting and analyzing behavioral cues from measured data, and developing models offering predictive and decision-making support. We highlight both the foundational speech and language processing building blocks as well as the novel processing and modeling opportunities. Using examples drawn from specific real-world applications ranging from literacy assessment and autism diagnostics to psychotherapy for addiction and marital well being, we illustrate behavioral informatics applications of these signal processing techniques that contribute to quantifying higher level, often subjectively described, human behavior in a domain-sensitive fashion. PMID:24039277

  2. Methods to Manipulate and Monitor Wnt Signaling in Human Pluripotent Stem Cells.

    Science.gov (United States)

    Huggins, Ian J; Brafman, David; Willert, Karl

    2016-01-01

    Human pluripotent stem cells (hPSCs) may revolutionize medical practice by providing: (a) a renewable source of cells for tissue replacement therapies, (b) a powerful system to model human diseases in a dish, and (c) a platform for examining efficacy and safety of novel drugs. Furthermore, these cells offer a unique opportunity to study early human development in vitro, in particular, the process by which a seemingly uniform cell population interacts to give rise to the three main embryonic lineages: ectoderm, endoderm. and mesoderm. This process of lineage allocation is regulated by a number of inductive signals that are mediated by growth factors, including FGF, TGFβ, and Wnt. In this book chapter, we introduce a set of tools, methods, and protocols to specifically manipulate the Wnt signaling pathway with the intention of altering the cell fate outcome of hPSCs.

  3. Naturally occuring nucleosome positioning signals in human exons and introns

    DEFF Research Database (Denmark)

    Baldi, Pierre; Brunak, Søren; Chauvin, Yves

    1996-01-01

    We describe the structural implications of a periodic pattern found in human exons and introns by hidden Markov models. We show that exons (besides the reading frame) have a specific sequential structure in the form of a pattern with triplet consensus non-T(A/T)G, and a minimal periodicity of rou...

  4. RAS signalling in energy metabolism and rare human diseases.

    Science.gov (United States)

    Dard, L; Bellance, N; Lacombe, D; Rossignol, R

    2018-05-08

    The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. Individuals with RASopathies, which are estimated to affect approximately 1/1000 human birth, share many overlapping characteristics, including cardiac malformations, short stature, neurocognitive impairment, craniofacial dysmorphy, cutaneous, musculoskeletal, and ocular abnormalities, hypotonia and a predisposition to developing cancer. Since the identification of the first RASopathy, type 1 neurofibromatosis (NF1), which is caused by the inactivation of neurofibromin 1, several other syndromes have been associated with mutations in the core components of the RAS-MAPK pathway. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), which was formerly called LEOPARD syndrome, Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). Here, we review current knowledge about the bioenergetics of the RASopathies and discuss the molecular control of energy homeostasis and mitochondrial physiology by the RAS pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

    OpenAIRE

    Tazearslan, Cagdas; Huang, Jing; Barzilai, Nir; Suh, Yousin

    2011-01-01

    Dampening of insulin/insulin like growth factor-1 (IGF1) signaling results in extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with reduced activity of the IGF1 receptor as measured in immortalized lymphoc...

  6. Mathematical modelling of SERK mediated BR signalling

    NARCIS (Netherlands)

    Esse, van G.W.

    2013-01-01

    Being sessile by nature plants are continuously challenged by biotic and abiotic stress factors. At the cellular level, different stimuli are perceived and translated to the desired response. In order to achieve this, signal transduction cascades have to be interlinked. Complex networks

  7. Efficient ECG Signal Compression Using Adaptive Heart Model

    National Research Council Canada - National Science Library

    Szilagyi, S

    2001-01-01

    This paper presents an adaptive, heart-model-based electrocardiography (ECG) compression method. After conventional pre-filtering the waves from the signal are localized and the model's parameters are determined...

  8. Improving traffic signal management and operations : a basic service model.

    Science.gov (United States)

    2009-12-01

    This report provides a guide for achieving a basic service model for traffic signal management and : operations. The basic service model is based on simply stated and defensible operational objectives : that consider the staffing level, expertise and...

  9. Signals and Systems in Biomedical Engineering Signal Processing and Physiological Systems Modeling

    CERN Document Server

    Devasahayam, Suresh R

    2013-01-01

    The use of digital signal processing is ubiquitous in the field of physiology and biomedical engineering. The application of such mathematical and computational tools requires a formal or explicit understanding of physiology. Formal models and analytical techniques are interlinked in physiology as in any other field. This book takes a unitary approach to physiological systems, beginning with signal measurement and acquisition, followed by signal processing, linear systems modelling, and computer simulations. The signal processing techniques range across filtering, spectral analysis and wavelet analysis. Emphasis is placed on fundamental understanding of the concepts as well as solving numerical problems. Graphs and analogies are used extensively to supplement the mathematics. Detailed models of nerve and muscle at the cellular and systemic levels provide examples for the mathematical methods and computer simulations. Several of the models are sufficiently sophisticated to be of value in understanding real wor...

  10. Using Noninvasive Wearable Computers to Recognize Human Emotions from Physiological Signals

    Directory of Open Access Journals (Sweden)

    Nasoz Fatma

    2004-01-01

    Full Text Available We discuss the strong relationship between affect and cognition and the importance of emotions in multimodal human computer interaction (HCI and user modeling. We introduce the overall paradigm for our multimodal system that aims at recognizing its users' emotions and at responding to them accordingly depending upon the current context or application. We then describe the design of the emotion elicitation experiment we conducted by collecting, via wearable computers, physiological signals from the autonomic nervous system (galvanic skin response, heart rate, temperature and mapping them to certain emotions (sadness, anger, fear, surprise, frustration, and amusement. We show the results of three different supervised learning algorithms that categorize these collected signals in terms of emotions, and generalize their learning to recognize emotions from new collections of signals. We finally discuss possible broader impact and potential applications of emotion recognition for multimodal intelligent systems.

  11. Human placental trophoblast invasion and differentiation: a particular focus on Wnt signalling

    Directory of Open Access Journals (Sweden)

    Martin eKnöfler

    2013-09-01

    Full Text Available Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signalling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signalling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β-catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signalling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signalling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β-catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signalling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodelling. Moreover, changes in Wnt signalling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signalling in physiological and abnormal

  12. MPD model for radar echo signal of hypersonic targets

    Directory of Open Access Journals (Sweden)

    Xu Xuefei

    2014-08-01

    Full Text Available The stop-and-go (SAG model is typically used for echo signal received by the radar using linear frequency modulation pulse compression. In this study, the authors demonstrate that this model is not applicable to hypersonic targets. Instead of SAG model, they present a more realistic echo signal model (moving-in-pulse duration (MPD for hypersonic targets. Following that, they evaluate the performances of pulse compression under the SAG and MPD models by theoretical analysis and simulations. They found that the pulse compression gain has an increase of 3 dB by using the MPD model compared with the SAG model in typical cases.

  13. Human mobility: Models and applications

    Science.gov (United States)

    Barbosa, Hugo; Barthelemy, Marc; Ghoshal, Gourab; James, Charlotte R.; Lenormand, Maxime; Louail, Thomas; Menezes, Ronaldo; Ramasco, José J.; Simini, Filippo; Tomasini, Marcello

    2018-03-01

    Recent years have witnessed an explosion of extensive geolocated datasets related to human movement, enabling scientists to quantitatively study individual and collective mobility patterns, and to generate models that can capture and reproduce the spatiotemporal structures and regularities in human trajectories. The study of human mobility is especially important for applications such as estimating migratory flows, traffic forecasting, urban planning, and epidemic modeling. In this survey, we review the approaches developed to reproduce various mobility patterns, with the main focus on recent developments. This review can be used both as an introduction to the fundamental modeling principles of human mobility, and as a collection of technical methods applicable to specific mobility-related problems. The review organizes the subject by differentiating between individual and population mobility and also between short-range and long-range mobility. Throughout the text the description of the theory is intertwined with real-world applications.

  14. Model developments for quantitative estimates of the benefits of the signals on nuclear power plant availability and economics

    International Nuclear Information System (INIS)

    Seong, Poong Hyun

    1993-01-01

    A novel framework for quantitative estimates of the benefits of signals on nuclear power plant availability and economics has been developed in this work. The models developed in this work quantify how the perfect signals affect the human operator's success in restoring the power plant to the desired state when it enters undesirable transients. Also, the models quantify the economic benefits of these perfect signals. The models have been applied to the condensate feedwater system of the nuclear power plant for demonstration. (Author)

  15. Large-signal modeling method for power FETs and diodes

    Energy Technology Data Exchange (ETDEWEB)

    Sun Lu; Wang Jiali; Wang Shan; Li Xuezheng; Shi Hui; Wang Na; Guo Shengping, E-mail: sunlu_1019@126.co [School of Electromechanical Engineering, Xidian University, Xi' an 710071 (China)

    2009-06-01

    Under a large signal drive level, a frequency domain black box model of the nonlinear scattering function is introduced into power FETs and diodes. A time domain measurement system and a calibration method based on a digital oscilloscope are designed to extract the nonlinear scattering function of semiconductor devices. The extracted models can reflect the real electrical performance of semiconductor devices and propose a new large-signal model to the design of microwave semiconductor circuits.

  16. Large-signal modeling method for power FETs and diodes

    International Nuclear Information System (INIS)

    Sun Lu; Wang Jiali; Wang Shan; Li Xuezheng; Shi Hui; Wang Na; Guo Shengping

    2009-01-01

    Under a large signal drive level, a frequency domain black box model of the nonlinear scattering function is introduced into power FETs and diodes. A time domain measurement system and a calibration method based on a digital oscilloscope are designed to extract the nonlinear scattering function of semiconductor devices. The extracted models can reflect the real electrical performance of semiconductor devices and propose a new large-signal model to the design of microwave semiconductor circuits.

  17. Contact-Free Heartbeat Signal for Human Identification and Forensics

    DEFF Research Database (Denmark)

    Nasrollahi, Kamal; Haque, Mohammad Ahsanul; Irani, Ramin

    2017-01-01

    The heartbeat signal, which is one of the physiological signals, is of great importance in many real-world applications, for example, in patient monitoring and biometric recognition. The traditional methods for measuring such this signal use contact-based sensors that need to be installed...... been developed for contact-free extraction of the heartbeat signal. We have recently used the contact-free measured heartbeat signal, for bio- metric recognition, and have obtained promising results, indicating the importance of these signals for biometrics recognition and also for forensics...

  18. A natural human hand model

    NARCIS (Netherlands)

    Van Nierop, O.A.; Van der Helm, A.; Overbeeke, K.J.; Djajadiningrat, T.J.P.

    2007-01-01

    We present a skeletal linked model of the human hand that has natural motion. We show how this can be achieved by introducing a new biology-based joint axis that simulates natural joint motion and a set of constraints that reduce an estimated 150 possible motions to twelve. The model is based on

  19. Modeling laser velocimeter signals as triply stochastic Poisson processes

    Science.gov (United States)

    Mayo, W. T., Jr.

    1976-01-01

    Previous models of laser Doppler velocimeter (LDV) systems have not adequately described dual-scatter signals in a manner useful for analysis and simulation of low-level photon-limited signals. At low photon rates, an LDV signal at the output of a photomultiplier tube is a compound nonhomogeneous filtered Poisson process, whose intensity function is another (slower) Poisson process with the nonstationary rate and frequency parameters controlled by a random flow (slowest) process. In the present paper, generalized Poisson shot noise models are developed for low-level LDV signals. Theoretical results useful in detection error analysis and simulation are presented, along with measurements of burst amplitude statistics. Computer generated simulations illustrate the difference between Gaussian and Poisson models of low-level signals.

  20. Coherence method of identifying signal noise model

    International Nuclear Information System (INIS)

    Vavrin, J.

    1981-01-01

    The noise analysis method is discussed in identifying perturbance models and their parameters by a stochastic analysis of the noise model of variables measured on a reactor. The analysis of correlations is made in the frequency region using coherence analysis methods. In identifying an actual specific perturbance, its model should be determined and recognized in a compound model of the perturbance system using the results of observation. The determination of the optimum estimate of the perturbance system model is based on estimates of related spectral densities which are determined from the spectral density matrix of the measured variables. Partial and multiple coherence, partial transfers, the power spectral densities of the input and output variables of the noise model are determined from the related spectral densities. The possibilities of applying the coherence identification methods were tested on a simple case of a simulated stochastic system. Good agreement was found of the initial analytic frequency filters and the transfers identified. (B.S.)

  1. Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling.

    Science.gov (United States)

    d'Hennezel, Eva; Abubucker, Sahar; Murphy, Leon O; Cullen, Thomas W

    2017-01-01

    Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immune stimulation generated by the microbiota such as the activation of Toll-like receptor 4 (TLR4) pathways by lipopolysaccharide (LPS). Indeed, gut microbial LPS is thought to be one of the most potent activators of innate immune signaling and an important mediator of the microbiome's influence on host physiology. In this study, we performed computational and experimental analyses of healthy human fecal samples to examine the TLR4 signaling capacity of the gut microbiota. These analyses revealed that an immunoinhibitory activity of LPS, conserved across the members of the order Bacteroidales and derived from an underacylated structural feature, silences TLR4 signaling for the entire consortium of organisms inhabiting the human gut. Comparative analysis of metagenomic data from the Human Microbiome Project and healthy-donor samples indicates that immune silencing via LPS is a microbe-intrinsic feature in all healthy adults. These findings challenge the current belief that robust TLR4 signaling is a feature of the microbiome and demonstrate that microbiome-derived LPS has the ability to facilitate host tolerance of gut microbes. These findings have broad implications for how we model host-microbe interactions and for our understanding of microbiome-linked disease. IMPORTANCE While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of intense research. This study shows that an important proinflammatory pathway that is commonly triggered by pathogenic bacteria upon interaction with the host is, in fact

  2. Modeling of Nonlinear Beat Signals of TAE's

    Science.gov (United States)

    Zhang, Bo; Berk, Herbert; Breizman, Boris; Zheng, Linjin

    2012-03-01

    Experiments on Alcator C-Mod reveal Toroidal Alfven Eigenmodes (TAE) together with signals at various beat frequencies, including those at twice the mode frequency. The beat frequencies are sidebands driven by quadratic nonlinear terms in the MHD equations. These nonlinear sidebands have not yet been quantified by any existing codes. We extend the AEGIS code to capture nonlinear effects by treating the nonlinear terms as a driving source in the linear MHD solver. Our goal is to compute the spatial structure of the sidebands for realistic geometry and q-profile, which can be directly compared with experiment in order to interpret the phase contrast imaging diagnostic measurements and to enable the quantitative determination of the Alfven wave amplitude in the plasma core

  3. Characterisation of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635 - explanation of high signal contrast in PET and an aid to biomathematical modelling

    International Nuclear Information System (INIS)

    Osman, Safiye; Lundkvist, Camilla; Pike, Victor W.; Halldin, Christer; McCarron, Julie A.; Swahn, Carl-Gunnar; Farde, Lars; Ginovart, Nathalie; Luthra, Sajinder K.; Gunn, Roger N.; Bench, Christopher J.; Sargent, Peter A.; Grasby, Paul M.

    1998-01-01

    N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11 C (t 1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT 1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [carbonyl- 11 C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT 1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT 1A receptors. [Carbonyl- 11 C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [O-methyl- 11 C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [carbonyl- 11 C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [Carbonyl- 11 C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [ 11 C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [carbonyl- 11 C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was

  4. Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

    Science.gov (United States)

    Gan, Yujun; Buckels, Ashiya; Liu, Ying; Zhang, Yue; Paterson, Andrew J.; Jiang, Jing; Zinn, Kurt R.

    2014-01-01

    GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed. PMID:25211187

  5. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

    OpenAIRE

    Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Redmond, T. Michael; Baehr, Wolfgang; Ding, Xi-Qin

    2014-01-01

    Photoreceptors degenerate in a wide array of hereditary retinal diseases and age-related macular degeneration. There is currently no treatment available for retinal degenerations. While outnumbered roughly 20:1 by rods in the human retina, it is the cones that mediate color vision and visual acuity, and their survival is critical for vision. In this communication, we investigate whether thyroid hormone (TH) signaling affects cone viability in retinal degeneration mouse models. TH signaling is...

  6. Characteristic parameters of electromagnetic signals from a human heart system

    International Nuclear Information System (INIS)

    Liu Xin-Yuan; Wang Yin; Zhang Su-Ming; Gao Hong-Lei; Pei Liu-Qing; Dai Yuan-Dong

    2011-01-01

    The electromagnetic field of a human heart system is a bioelectromagnetic field. Electrocardiography (ECG) and magnetocardiography (MCG) are both carriers of electromagnetic information about the cardiac system, and they are nonstationary signals. In this study, ECG and MCG data from healthy subjects are acquired; the MCG data are captured using a high-T c radio frequency superconducting quantum interference device (HTc rf SQUIDs) and the QRS complexes in these data are analysed by the evolutionary spectrum analysis method. The results show that the quality factor Q and the central frequency f z of the QRS complex evolutionary spectrum are the characteristic parameters (CHPs) of ECG and MCG in the time—frequency domain. The confidence intervals of the mean values of the CHPs are estimated by the Student t distribution method in mathematical statistics. We believe that there are threshold ranges of the mean values of Q and f z for healthy subjects. We have postulated the following criterion: if the mean values of CHPs are in the proper ranges, the cardiac system is in a normal condition and it possesses the capability of homeostasis. In contrast, if the mean values of the CHPs do not lie in the proper ranges, the homeostasis of the cardiac system is lacking and some cardiac disease may follow. The results and procedure of MCG CHPs in the study afford a technological route for the application of HTc rf SQUIDs in cardiology. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  7. Dialectical Model of Human Nature

    OpenAIRE

    Cachat, Jonathan

    2013-01-01

    The DMoHN is a graphical representation of my current understanding and conceptualization of human nature, in addition to embodying the guiding ethos of social neuroscience. The dialectic is a logic, or way of thinking that joins opposite elements together in a uniting fashion to create emergent attributes not present in the elements alone. The dialectical structure of this model explicitly links Culture and Biology within the human brain in order to convey the symbiotic and dynamic interacti...

  8. Modelling of Signal - Level Crossing System

    Directory of Open Access Journals (Sweden)

    Daniel Novak

    2006-01-01

    Full Text Available The author presents an object-oriented model of a railway level-crossing system created for the purpose of functional requirements specification. Unified Modelling Language (UML, version 1.4, which enables specification, visualisation, construction and documentation of software system artefacts, was used. The main attention was paid to analysis and design phases. The former phase resulted in creation of use case diagrams and sequential diagrams, the latter in creation of class/object diagrams and statechart diagrams.

  9. HP Memristor mathematical model for periodic signals and DC

    KAUST Repository

    Radwan, Ahmed G.; Salama, Khaled N.; Zidan, Mohammed A.

    2012-01-01

    the formulas for any general square wave. The limiting conditions for saturation are also provided in case of either DC or periodic signals. The derived equations are compared to the SPICE model of the Memristor showing a perfect match.

  10. Comparison of Linear Prediction Models for Audio Signals

    Directory of Open Access Journals (Sweden)

    2009-03-01

    Full Text Available While linear prediction (LP has become immensely popular in speech modeling, it does not seem to provide a good approach for modeling audio signals. This is somewhat surprising, since a tonal signal consisting of a number of sinusoids can be perfectly predicted based on an (all-pole LP model with a model order that is twice the number of sinusoids. We provide an explanation why this result cannot simply be extrapolated to LP of audio signals. If noise is taken into account in the tonal signal model, a low-order all-pole model appears to be only appropriate when the tonal components are uniformly distributed in the Nyquist interval. Based on this observation, different alternatives to the conventional LP model can be suggested. Either the model should be changed to a pole-zero, a high-order all-pole, or a pitch prediction model, or the conventional LP model should be preceded by an appropriate frequency transform, such as a frequency warping or downsampling. By comparing these alternative LP models to the conventional LP model in terms of frequency estimation accuracy, residual spectral flatness, and perceptual frequency resolution, we obtain several new and promising approaches to LP-based audio modeling.

  11. Transduction motif analysis of gastric cancer based on a human signaling network

    Energy Technology Data Exchange (ETDEWEB)

    Liu, G.; Li, D.Z.; Jiang, C.S.; Wang, W. [Fuzhou General Hospital of Nanjing Command, Department of Gastroenterology, Fuzhou, China, Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou (China)

    2014-04-04

    To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

  12. Pharmacological migraine provocation: a human model of migraine

    DEFF Research Database (Denmark)

    Ashina, Messoud; Hansen, Jakob Møller

    2010-01-01

    for migraine mechanisms. So far, however, animal models cannot predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy, the headache- or migraine-provoking property of naturally occurring signaling molecules can be tested in a human model....... If a naturally occurring substance can provoke migraine in human patients, then it is likely, although not certain, that blocking its effect will be effective in the treatment of acute migraine attacks. To this end, a human in vivo model of experimental headache and migraine in humans has been developed...

  13. Covert Sexual Signaling: Human Flirtation and Implications for other Social Species

    Directory of Open Access Journals (Sweden)

    Andrew Gersick

    2014-07-01

    Full Text Available According to signaling theory and a large body of supporting evidence, males across many taxa produce courtship signals that honestly advertise their quality. The cost of producing or performing these signals maintains signal honesty, such that females are typically able to choose the best males by selecting those that produce the loudest, brightest, longest, or otherwise highest-intensity signals, using signal strength as a measure of quality. Set against this background, human flirting behavior, characterized by its frequent subtlety or covertness, is mysterious. Here we propose that the explanation for subtle and ambiguous signals in human courtship lies in socially imposed costs that (a vary with social context and (b are amplified by the unusual ways in which language makes all interactions potentially public. Flirting is a class of courtship signaling that conveys the signaler's intentions and desirability to the intended receiver while minimizing the costs that would accompany an overt courtship attempt. This proposal explains humans' taxonomically unusual courtship displays and generates a number of novel predictions for both humans and non-human social animals. Individuals who are courting should vary the intensity of their signals to suit the level of risk attached to the particular social configuration, and receivers may assess this flexible matching of signal to context as an indicator of the signaler's broader behavioral flexibility and social intelligence.

  14. Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

    Science.gov (United States)

    Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

    2010-01-01

    The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

  15. Human Modeling for Ground Processing Human Factors Engineering Analysis

    Science.gov (United States)

    Stambolian, Damon B.; Lawrence, Brad A.; Stelges, Katrine S.; Steady, Marie-Jeanne O.; Ridgwell, Lora C.; Mills, Robert E.; Henderson, Gena; Tran, Donald; Barth, Tim

    2011-01-01

    There have been many advancements and accomplishments over the last few years using human modeling for human factors engineering analysis for design of spacecraft. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the human modeling currently used at Kennedy Space Center (KSC), and to explain the future plans for human modeling for future spacecraft designs

  16. Model-based Bayesian signal extraction algorithm for peripheral nerves

    Science.gov (United States)

    Eggers, Thomas E.; Dweiri, Yazan M.; McCallum, Grant A.; Durand, Dominique M.

    2017-10-01

    Objective. Multi-channel cuff electrodes have recently been investigated for extracting fascicular-level motor commands from mixed neural recordings. Such signals could provide volitional, intuitive control over a robotic prosthesis for amputee patients. Recent work has demonstrated success in extracting these signals in acute and chronic preparations using spatial filtering techniques. These extracted signals, however, had low signal-to-noise ratios and thus limited their utility to binary classification. In this work a new algorithm is proposed which combines previous source localization approaches to create a model based method which operates in real time. Approach. To validate this algorithm, a saline benchtop setup was created to allow the precise placement of artificial sources within a cuff and interference sources outside the cuff. The artificial source was taken from five seconds of chronic neural activity to replicate realistic recordings. The proposed algorithm, hybrid Bayesian signal extraction (HBSE), is then compared to previous algorithms, beamforming and a Bayesian spatial filtering method, on this test data. An example chronic neural recording is also analyzed with all three algorithms. Main results. The proposed algorithm improved the signal to noise and signal to interference ratio of extracted test signals two to three fold, as well as increased the correlation coefficient between the original and recovered signals by 10-20%. These improvements translated to the chronic recording example and increased the calculated bit rate between the recovered signals and the recorded motor activity. Significance. HBSE significantly outperforms previous algorithms in extracting realistic neural signals, even in the presence of external noise sources. These results demonstrate the feasibility of extracting dynamic motor signals from a multi-fascicled intact nerve trunk, which in turn could extract motor command signals from an amputee for the end goal of

  17. A simple statistical signal loss model for deep underground garage

    DEFF Research Database (Denmark)

    Nguyen, Huan Cong; Gimenez, Lucas Chavarria; Kovacs, Istvan

    2016-01-01

    In this paper we address the channel modeling aspects for a deep-indoor scenario with extreme coverage conditions in terms of signal losses, namely underground garage areas. We provide an in-depth analysis in terms of path loss (gain) and large scale signal shadowing, and a propose simple...... propagation model which can be used to predict cellular signal levels in similar deep-indoor scenarios. The proposed frequency-independent floor attenuation factor (FAF) is shown to be in range of 5.2 dB per meter deep....

  18. Wires in the soup: quantitative models of cell signaling

    Science.gov (United States)

    Cheong, Raymond; Levchenko, Andre

    2014-01-01

    Living cells are capable of extracting information from their environments and mounting appropriate responses to a variety of associated challenges. The underlying signal transduction networks enabling this can be quite complex, necessitating for their unraveling by sophisticated computational modeling coupled with precise experimentation. Although we are still at the beginning of this process, some recent examples of integrative analysis of cell signaling are very encouraging. This review highlights the case of the NF-κB pathway in order to illustrate how a quantitative model of a signaling pathway can be gradually constructed through continuous experimental validation, and what lessons one might learn from such exercises. PMID:18291655

  19. THE SIGNAL APPROACH TO MODELLING THE BALANCE OF PAYMENT CRISIS

    Directory of Open Access Journals (Sweden)

    O. Chernyak

    2016-12-01

    Full Text Available The paper considers and presents synthesis of theoretical models of balance of payment crisis and investigates the most effective ways to model the crisis in Ukraine. For mathematical formalization of balance of payment crisis, comparative analysis of the effectiveness of different calculation methods of Exchange Market Pressure Index was performed. A set of indicators that signal the growing likelihood of balance of payments crisis was defined using signal approach. With the help of minimization function thresholds indicators were selected, the crossing of which signalize increase in the probability of balance of payment crisis.

  20. Small signal modeling of wind farms

    DEFF Research Database (Denmark)

    Ebrahimzadeh, Esmaeil; Blaabjerg, Frede; Wang, Xiongfei

    2017-01-01

    -Input Multi-Output (MIMO) dynamic system, where the current control loops with Phase-Locked Loops (PLLs) are linearized around an operating point. Each sub-module of the wind farm is modeled as a 2×2 admittance matrix in dq-domain and all are combined together by using a dq nodal admittance matrix....... The frequency and damping of the oscillatory modes are calculated by finding the poles of the introduced MIMO matrix. Time-domain simulation results obtained from a 400-MW wind farm are used to verify the effectiveness of the presented model....

  1. An accurate and simple large signal model of HEMT

    DEFF Research Database (Denmark)

    Liu, Qing

    1989-01-01

    A large-signal model of discrete HEMTs (high-electron-mobility transistors) has been developed. It is simple and suitable for SPICE simulation of hybrid digital ICs. The model parameters are extracted by using computer programs and data provided by the manufacturer. Based on this model, a hybrid...

  2. Semiconductor Modeling For Simulating Signal, Power, and Electromagneticintegrity

    CERN Document Server

    Leventhal, Roy

    2006-01-01

    Assists engineers in designing high-speed circuits. The emphasis is on semiconductor modeling, with PCB transmission line effects, equipment enclosure effects, and other modeling issues discussed as needed. This text addresses practical considerations, including process variation, model accuracy, validation and verification, and signal integrity.

  3. Vibration Signal Forecasting on Rotating Machinery by means of Signal Decomposition and Neurofuzzy Modeling

    Directory of Open Access Journals (Sweden)

    Daniel Zurita-Millán

    2016-01-01

    Full Text Available Vibration monitoring plays a key role in the industrial machinery reliability since it allows enhancing the performance of the machinery under supervision through the detection of failure modes. Thus, vibration monitoring schemes that give information regarding future condition, that is, prognosis approaches, are of growing interest for the scientific and industrial communities. This work proposes a vibration signal prognosis methodology, applied to a rotating electromechanical system and its associated kinematic chain. The method combines the adaptability of neurofuzzy modeling with a signal decomposition strategy to model the patterns of the vibrations signal under different fault scenarios. The model tuning is performed by means of Genetic Algorithms along with a correlation based interval selection procedure. The performance and effectiveness of the proposed method are validated experimentally with an electromechanical test bench containing a kinematic chain. The results of the study indicate the suitability of the method for vibration forecasting in complex electromechanical systems and their associated kinematic chains.

  4. Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad.

    Directory of Open Access Journals (Sweden)

    Andrew J Childs

    Full Text Available The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA. Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may

  5. Retinoic Acid Signalling and the Control of Meiotic Entry in the Human Fetal Gonad

    Science.gov (United States)

    Kinnell, Hazel L.; Anderson, Richard A.; Saunders, Philippa T. K.

    2011-01-01

    The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8–9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in

  6. Discrete dynamic modeling of T cell survival signaling networks

    Science.gov (United States)

    Zhang, Ranran

    2009-03-01

    Biochemistry-based frameworks are often not applicable for the modeling of heterogeneous regulatory systems that are sparsely documented in terms of quantitative information. As an alternative, qualitative models assuming a small set of discrete states are gaining acceptance. This talk will present a discrete dynamic model of the signaling network responsible for the survival and long-term competence of cytotoxic T cells in the blood cancer T-LGL leukemia. We integrated the signaling pathways involved in normal T cell activation and the known deregulations of survival signaling in leukemic T-LGL, and formulated the regulation of each network element as a Boolean (logic) rule. Our model suggests that the persistence of two signals is sufficient to reproduce all known deregulations in leukemic T-LGL. It also indicates the nodes whose inactivity is necessary and sufficient for the reversal of the T-LGL state. We have experimentally validated several model predictions, including: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NFκB are essential for the long-term survival of T cells in T-LGL leukemia. (iii) T box expressed in T cells (T-bet) is constitutively activated in the T-LGL state. The model has identified potential therapeutic targets for T-LGL leukemia and can be used for generating long-term competent CTL necessary for tumor and cancer vaccine development. The success of this model, and of other discrete dynamic models, suggests that the organization of signaling networks has an determining role in their dynamics. Reference: R. Zhang, M. V. Shah, J. Yang, S. B. Nyland, X. Liu, J. K. Yun, R. Albert, T. P. Loughran, Jr., Network Model of Survival Signaling in LGL Leukemia, PNAS 105, 16308-16313 (2008).

  7. Collective signaling behavior in a networked-oscillator model

    Science.gov (United States)

    Liu, Z.-H.; Hui, P. M.

    2007-09-01

    We propose and study the collective behavior of a model of networked signaling objects that incorporates several ingredients of real-life systems. These ingredients include spatial inhomogeneity with grouping of signaling objects, signal attenuation with distance, and delayed and impulsive coupling between non-identical signaling objects. Depending on the coupling strength and/or time-delay effect, the model exhibits completely, partially, and locally collective signaling behavior. In particular, a correlated signaling (CS) behavior is observed in which there exist time durations when nearly a constant fraction of oscillators in the system are in the signaling state. These time durations are much longer than the duration of a spike when a single oscillator signals, and they are separated by regular intervals in which nearly all oscillators are silent. Such CS behavior is similar to that observed in biological systems such as fireflies, cicadas, crickets, and frogs. The robustness of the CS behavior against noise is also studied. It is found that properly adjusting the coupling strength and noise level could enhance the correlated behavior.

  8. Analysis of a dynamic model of guard cell signaling reveals the stability of signal propagation

    Science.gov (United States)

    Gan, Xiao; Albert, RéKa

    Analyzing the long-term behaviors (attractors) of dynamic models of biological systems can provide valuable insight into biological phenotypes and their stability. We identified the long-term behaviors of a multi-level, 70-node discrete dynamic model of the stomatal opening process in plants. We reduce the model's huge state space by reducing unregulated nodes and simple mediator nodes, and by simplifying the regulatory functions of selected nodes while keeping the model consistent with experimental observations. We perform attractor analysis on the resulting 32-node reduced model by two methods: 1. converting it into a Boolean model, then applying two attractor-finding algorithms; 2. theoretical analysis of the regulatory functions. We conclude that all nodes except two in the reduced model have a single attractor; and only two nodes can admit oscillations. The multistability or oscillations do not affect the stomatal opening level in any situation. This conclusion applies to the original model as well in all the biologically meaningful cases. We further demonstrate the robustness of signal propagation by showing that a large percentage of single-node knockouts does not affect the stomatal opening level. Thus, we conclude that the complex structure of this signal transduction network provides multiple information propagation pathways while not allowing extensive multistability or oscillations, resulting in robust signal propagation. Our innovative combination of methods offers a promising way to analyze multi-level models.

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

    Directory of Open Access Journals (Sweden)

    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

  10. Standardisation of digital human models.

    Science.gov (United States)

    Paul, Gunther; Wischniewski, Sascha

    2012-01-01

    Digital human models (DHM) have evolved as useful tools for ergonomic workplace design and product development, and found in various industries and education. DHM systems which dominate the market were developed for specific purposes and differ significantly, which is not only reflected in non-compatible results of DHM simulations, but also provoking misunderstanding of how DHM simulations relate to real world problems. While DHM developers are restricted by uncertainty about the user need and lack of model data related standards, users are confined to one specific product and cannot exchange results, or upgrade to another DHM system, as their previous results would be rendered worthless. Furthermore, origin and validity of anthropometric and biomechanical data is not transparent to the user. The lack of standardisation in DHM systems has become a major roadblock in further system development, affecting all stakeholders in the DHM industry. Evidently, a framework for standardising digital human models is necessary to overcome current obstructions. Practitioner Summary: This short communication addresses a standardisation issue for digital human models, which has been addressed at the International Ergonomics Association Technical Committee for Human Simulation and Virtual Environments. It is the outcome of a workshop at the DHM 2011 symposium in Lyon, which concluded steps towards DHM standardisation that need to be taken.

  11. Modelling biased human trust dynamics

    NARCIS (Netherlands)

    Hoogendoorn, M.; Jaffry, S.W.; Maanen, P.P. van; Treur, J.

    2013-01-01

    Abstract. Within human trust related behaviour, according to the literature from the domains of Psychology and Social Sciences often non-rational behaviour can be observed. Current trust models that have been developed typically do not incorporate non-rational elements in the trust formation

  12. Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies.

    Directory of Open Access Journals (Sweden)

    Zoe Waibler

    Full Text Available Superagonistic CD28 antibodies (CD28SAs activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-gamma and TNF-alpha. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-gamma and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.

  13. AR-Signaling in Human Malignancies: Prostate Cancer and Beyond

    Directory of Open Access Journals (Sweden)

    Michael T. Schweizer

    2017-01-01

    Full Text Available In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.

  14. Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development

    OpenAIRE

    Jenkins, Dagan; Winyard, Paul J D; Woolf, Adrian S.

    2007-01-01

    Studies of mouse mutants have demonstrated that Sonic hedgehog (SHH) signalling has a functional role in morphogenesis and differentiation at multiple sites within the forming urinary tract, and urinary tract malformations have been reported in humans with mutations that disrupt SHH signalling. However, there is only strikingly sparse and fragmentary information about the expression of SHH and associated signalling genes in normal human urinary tract development. We used immunohistochemistry ...

  15. Signal classification using global dynamical models, Part I: Theory

    International Nuclear Information System (INIS)

    Kadtke, J.; Kremliovsky, M.

    1996-01-01

    Detection and classification of signals is one of the principal areas of signal processing, and the utilization of nonlinear information has long been considered as a way of improving performance beyond standard linear (e.g. spectral) techniques. Here, we develop a method for using global models of chaotic dynamical systems theory to define a signal classification processing chain, which is sensitive to nonlinear correlations in the data. We use it to demonstrate classification in high noise regimes (negative SNR), and argue that classification probabilities can be directly computed from ensemble statistics in the model coefficient space. We also develop a modification for non-stationary signals (i.e. transients) using non-autonomous ODEs. In Part II of this paper, we demonstrate the analysis on actual open ocean acoustic data from marine biologics. copyright 1996 American Institute of Physics

  16. Small-signal model for the series resonant converter

    Science.gov (United States)

    King, R. J.; Stuart, T. A.

    1985-01-01

    The results of a previous discrete-time model of the series resonant dc-dc converter are reviewed and from these a small signal dynamic model is derived. This model is valid for low frequencies and is based on the modulation of the diode conduction angle for control. The basic converter is modeled separately from its output filter to facilitate the use of these results for design purposes. Experimental results are presented.

  17. Mixed-signal instrumentation for large-signal device characterization and modelling

    NARCIS (Netherlands)

    Marchetti, M.

    2013-01-01

    This thesis concentrates on the development of advanced large-signal measurement and characterization tools to support technology development, model extraction and validation, and power amplifier (PA) designs that address the newly introduced third and fourth generation (3G and 4G) wideband

  18. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2010-01-01

    have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

  19. Contact-Free Heartbeat Signal for Human Identification and Forensics

    DEFF Research Database (Denmark)

    Nasrollahi, Kamal; Haque, Mohammad Ahsanul; Irani, Ramin

    2017-01-01

    on the subject’s body. Though it might be possible to use touch-based sensors in applications like patient monitoring, it won’t be that easy to use them in identification and forensics applications, espe- cially if subjects are not cooperative. To deal with this problem, recently computer vision techniques have......The heartbeat signal, which is one of the physiological signals, is of great importance in many real-world applications, for example, in patient monitoring and biometric recognition. The traditional methods for measuring such this signal use contact-based sensors that need to be installed...

  20. Human Age Recognition by Electrocardiogram Signal Based on Artificial Neural Network

    Science.gov (United States)

    Dasgupta, Hirak

    2016-12-01

    The objective of this work is to make a neural network function approximation model to detect human age from the electrocardiogram (ECG) signal. The input vectors of the neural network are the Katz fractal dimension of the ECG signal, frequencies in the QRS complex, male or female (represented by numeric constant) and the average of successive R-R peak distance of a particular ECG signal. The QRS complex has been detected by short time Fourier transform algorithm. The successive R peak has been detected by, first cutting the signal into periods by auto-correlation method and then finding the absolute of the highest point in each period. The neural network used in this problem consists of two layers, with Sigmoid neuron in the input and linear neuron in the output layer. The result shows the mean of errors as -0.49, 1.03, 0.79 years and the standard deviation of errors as 1.81, 1.77, 2.70 years during training, cross validation and testing with unknown data sets, respectively.

  1. An Analysis/Synthesis System of Audio Signal with Utilization of an SN Model

    Directory of Open Access Journals (Sweden)

    G. Rozinaj

    2004-12-01

    Full Text Available An SN (sinusoids plus noise model is a spectral model, in which theperiodic components of the sound are represented by sinusoids withtime-varying frequencies, amplitudes and phases. The remainingnon-periodic components are represented by a filtered noise. Thesinusoidal model utilizes physical properties of musical instrumentsand the noise model utilizes the human inability to perceive the exactspectral shape or the phase of stochastic signals. SN modeling can beapplied in a compression, transformation, separation of sounds, etc.The designed system is based on methods used in the SN modeling. Wehave proposed a model that achieves good results in audio perception.Although many systems do not save phases of the sinusoids, they areimportant for better modelling of transients, for the computation ofresidual and last but not least for stereo signals, too. One of thefundamental properties of the proposed system is the ability of thesignal reconstruction not only from the amplitude but from the phasepoint of view, as well.

  2. Electromagnetic modeling method for eddy current signal analysis

    International Nuclear Information System (INIS)

    Lee, D. H.; Jung, H. K.; Cheong, Y. M.; Lee, Y. S.; Huh, H.; Yang, D. J.

    2004-10-01

    An electromagnetic modeling method for eddy current signal analysis is necessary before an experiment is performed. Electromagnetic modeling methods consists of the analytical method and the numerical method. Also, the numerical methods can be divided by Finite Element Method(FEM), Boundary Element Method(BEM) and Volume Integral Method(VIM). Each modeling method has some merits and demerits. Therefore, the suitable modeling method can be chosen by considering the characteristics of each modeling. This report explains the principle and application of each modeling method and shows the comparison modeling programs

  3. Extremely low frequency electromagnetic field exposure does not modulate Toll-like receptor signaling in human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Kleijn, de S.; Bouwens, M.; Verburg-van Kemenade, B.M.L.; Cuppen, J.J.M.; Ferwerda, G.; Hermans, P.

    2011-01-01

    The effects of extremely low frequency electromagnetic fields (ELF-EMF) on human health remain unclear. It has been reported that ELF-EMF may modulate the innate immune response to microorganisms in animal models and mammalian cell-lines. With the recently gained insight in innate immune signaling

  4. Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling.

    Science.gov (United States)

    Mao, Suifang; Shah, Alok S; Moninger, Thomas O; Ostedgaard, Lynda S; Lu, Lin; Tang, Xiao Xiao; Thornell, Ian M; Reznikov, Leah R; Ernst, Sarah E; Karp, Philip H; Tan, Ping; Keshavjee, Shaf; Abou Alaiwa, Mahmoud H; Welsh, Michael J

    2018-02-06

    Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including Gα i and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. Copyright © 2018 the Author(s). Published by PNAS.

  5. Solution structure of the human signaling protein RACK1

    Directory of Open Access Journals (Sweden)

    Papa Priscila F

    2010-06-01

    Full Text Available Abstract Background The adaptor protein RACK1 (receptor of activated kinase 1 was originally identified as an anchoring protein for protein kinase C. RACK1 is a 36 kDa protein, and is composed of seven WD repeats which mediate its protein-protein interactions. RACK1 is ubiquitously expressed and has been implicated in diverse cellular processes involving: protein translation regulation, neuropathological processes, cellular stress, and tissue development. Results In this study we performed a biophysical analysis of human RACK1 with the aim of obtaining low resolution structural information. Small angle X-ray scattering (SAXS experiments demonstrated that human RACK1 is globular and monomeric in solution and its low resolution structure is strikingly similar to that of an homology model previously calculated by us and to the crystallographic structure of RACK1 isoform A from Arabidopsis thaliana. Both sedimentation velocity and sedimentation equilibrium analytical ultracentrifugation techniques showed that RACK1 is predominantly a monomer of around 37 kDa in solution, but also presents small amounts of oligomeric species. Moreover, hydrodynamic data suggested that RACK1 has a slightly asymmetric shape. The interaction of RACK1 and Ki-1/57 was tested by sedimentation equilibrium. The results suggested that the association between RACK1 and Ki-1/57(122-413 follows a stoichiometry of 1:1. The binding constant (KB observed for RACK1-Ki-1/57(122-413 interaction was of around (1.5 ± 0.2 × 106 M-1 and resulted in a dissociation constant (KD of (0.7 ± 0.1 × 10-6 M. Moreover, the fluorescence data also suggests that the interaction may occur in a cooperative fashion. Conclusion Our SAXS and analytical ultracentrifugation experiments indicated that RACK1 is predominantly a monomer in solution. RACK1 and Ki-1/57(122-413 interact strongly under the tested conditions.

  6. Endogenous Nur77 Is a Specific Indicator of Antigen Receptor Signaling in Human T and B Cells.

    Science.gov (United States)

    Ashouri, Judith F; Weiss, Arthur

    2017-01-15

    Distinguishing true Ag-stimulated lymphocytes from bystanders activated by the inflammatory milieu has been difficult. Nur77 is an immediate early gene whose expression is rapidly upregulated by TCR signaling in murine T cells and human thymocytes. Nur77-GFP transgenes serve as specific TCR and BCR signaling reporters in murine transgenic models. In this study, we demonstrate that endogenous Nur77 protein expression can serve as a reporter of TCR and BCR specific signaling in human PBMCs. Nur77 protein amounts were assessed by immunofluorescence and flow cytometry in T and B cells isolated from human PBMCs obtained from healthy donors that had been stimulated by their respective Ag receptors. We demonstrate that endogenous Nur77 is a more specific reporter of Ag-specific signaling events than the commonly used CD69 activation marker in both human T and B cells. This is reflective of the disparity in signaling pathways that regulate the expression of Nur77 and CD69. Assessing endogenous Nur77 protein expression has great potential to identify Ag-activated lymphocytes in human disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  7. Reduced modeling of signal transduction – a modular approach

    Directory of Open Access Journals (Sweden)

    Ederer Michael

    2007-09-01

    Full Text Available Abstract Background Combinatorial complexity is a challenging problem in detailed and mechanistic mathematical modeling of signal transduction. This subject has been discussed intensively and a lot of progress has been made within the last few years. A software tool (BioNetGen was developed which allows an automatic rule-based set-up of mechanistic model equations. In many cases these models can be reduced by an exact domain-oriented lumping technique. However, the resulting models can still consist of a very large number of differential equations. Results We introduce a new reduction technique, which allows building modularized and highly reduced models. Compared to existing approaches further reduction of signal transduction networks is possible. The method also provides a new modularization criterion, which allows to dissect the model into smaller modules that are called layers and can be modeled independently. Hallmarks of the approach are conservation relations within each layer and connection of layers by signal flows instead of mass flows. The reduced model can be formulated directly without previous generation of detailed model equations. It can be understood and interpreted intuitively, as model variables are macroscopic quantities that are converted by rates following simple kinetics. The proposed technique is applicable without using complex mathematical tools and even without detailed knowledge of the mathematical background. However, we provide a detailed mathematical analysis to show performance and limitations of the method. For physiologically relevant parameter domains the transient as well as the stationary errors caused by the reduction are negligible. Conclusion The new layer based reduced modeling method allows building modularized and strongly reduced models of signal transduction networks. Reduced model equations can be directly formulated and are intuitively interpretable. Additionally, the method provides very good

  8. HP Memristor mathematical model for periodic signals and DC

    KAUST Repository

    Radwan, Ahmed G.

    2012-07-28

    In this paper mathematical models of the HP Memristor for DC and periodic signal inputs are provided. The need for a rigid model for the Memristor using conventional current and voltage quantities is essential for the development of many promising Memristors\\' applications. Unlike the previous works, which focuses on the sinusoidal input waveform, we derived rules for any periodic signals in general in terms of voltage and current. Square and triangle waveforms are studied explicitly, extending the formulas for any general square wave. The limiting conditions for saturation are also provided in case of either DC or periodic signals. The derived equations are compared to the SPICE model of the Memristor showing a perfect match.

  9. Signal and noise modeling in confocal laser scanning fluorescence microscopy.

    Science.gov (United States)

    Herberich, Gerlind; Windoffer, Reinhard; Leube, Rudolf E; Aach, Til

    2012-01-01

    Fluorescence confocal laser scanning microscopy (CLSM) has revolutionized imaging of subcellular structures in biomedical research by enabling the acquisition of 3D time-series of fluorescently-tagged proteins in living cells, hence forming the basis for an automated quantification of their morphological and dynamic characteristics. Due to the inherently weak fluorescence, CLSM images exhibit a low SNR. We present a novel model for the transfer of signal and noise in CLSM that is both theoretically sound as well as corroborated by a rigorous analysis of the pixel intensity statistics via measurement of the 3D noise power spectra, signal-dependence and distribution. Our model provides a better fit to the data than previously proposed models. Further, it forms the basis for (i) the simulation of the CLSM imaging process indispensable for the quantitative evaluation of CLSM image analysis algorithms, (ii) the application of Poisson denoising algorithms and (iii) the reconstruction of the fluorescence signal.

  10. Corrected Four-Sphere Head Model for EEG Signals.

    Science.gov (United States)

    Næss, Solveig; Chintaluri, Chaitanya; Ness, Torbjørn V; Dale, Anders M; Einevoll, Gaute T; Wójcik, Daniel K

    2017-01-01

    The EEG signal is generated by electrical brain cell activity, often described in terms of current dipoles. By applying EEG forward models we can compute the contribution from such dipoles to the electrical potential recorded by EEG electrodes. Forward models are key both for generating understanding and intuition about the neural origin of EEG signals as well as inverse modeling, i.e., the estimation of the underlying dipole sources from recorded EEG signals. Different models of varying complexity and biological detail are used in the field. One such analytical model is the four-sphere model which assumes a four-layered spherical head where the layers represent brain tissue, cerebrospinal fluid (CSF), skull, and scalp, respectively. While conceptually clear, the mathematical expression for the electric potentials in the four-sphere model is cumbersome, and we observed that the formulas presented in the literature contain errors. Here, we derive and present the correct analytical formulas with a detailed derivation. A useful application of the analytical four-sphere model is that it can serve as ground truth to test the accuracy of numerical schemes such as the Finite Element Method (FEM). We performed FEM simulations of the four-sphere head model and showed that they were consistent with the corrected analytical formulas. For future reference we provide scripts for computing EEG potentials with the four-sphere model, both by means of the correct analytical formulas and numerical FEM simulations.

  11. Corrected Four-Sphere Head Model for EEG Signals

    Directory of Open Access Journals (Sweden)

    Solveig Næss

    2017-10-01

    Full Text Available The EEG signal is generated by electrical brain cell activity, often described in terms of current dipoles. By applying EEG forward models we can compute the contribution from such dipoles to the electrical potential recorded by EEG electrodes. Forward models are key both for generating understanding and intuition about the neural origin of EEG signals as well as inverse modeling, i.e., the estimation of the underlying dipole sources from recorded EEG signals. Different models of varying complexity and biological detail are used in the field. One such analytical model is the four-sphere model which assumes a four-layered spherical head where the layers represent brain tissue, cerebrospinal fluid (CSF, skull, and scalp, respectively. While conceptually clear, the mathematical expression for the electric potentials in the four-sphere model is cumbersome, and we observed that the formulas presented in the literature contain errors. Here, we derive and present the correct analytical formulas with a detailed derivation. A useful application of the analytical four-sphere model is that it can serve as ground truth to test the accuracy of numerical schemes such as the Finite Element Method (FEM. We performed FEM simulations of the four-sphere head model and showed that they were consistent with the corrected analytical formulas. For future reference we provide scripts for computing EEG potentials with the four-sphere model, both by means of the correct analytical formulas and numerical FEM simulations.

  12. Road Impedance Model Study under the Control of Intersection Signal

    Directory of Open Access Journals (Sweden)

    Yunlin Luo

    2015-01-01

    Full Text Available Road traffic impedance model is a difficult and critical point in urban traffic assignment and route guidance. The paper takes a signalized intersection as the research object. On the basis of traditional traffic wave theory including the implementation of traffic wave model and the analysis of vehicles’ gathering and dissipating, the road traffic impedance model is researched by determining the basic travel time and waiting delay time. Numerical example results have proved that the proposed model in this paper has received better calculation performance compared to existing model, especially in flat hours. The values of mean absolute percentage error (MAPE and mean absolute deviation (MAD are separately reduced by 3.78% and 2.62 s. It shows that the proposed model has feasibility and availability in road traffic impedance under intersection signal.

  13. Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

    Directory of Open Access Journals (Sweden)

    Silvia Mazzotta

    2016-10-01

    Full Text Available Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

  14. Stochastic Modelling as a Tool for Seismic Signals Segmentation

    Directory of Open Access Journals (Sweden)

    Daniel Kucharczyk

    2016-01-01

    Full Text Available In order to model nonstationary real-world processes one can find appropriate theoretical model with properties following the analyzed data. However in this case many trajectories of the analyzed process are required. Alternatively, one can extract parts of the signal that have homogenous structure via segmentation. The proper segmentation can lead to extraction of important features of analyzed phenomena that cannot be described without the segmentation. There is no one universal method that can be applied for all of the phenomena; thus novel methods should be invented for specific cases. They might address specific character of the signal in different domains (time, frequency, time-frequency, etc.. In this paper we propose two novel segmentation methods that take under consideration the stochastic properties of the analyzed signals in time domain. Our research is motivated by the analysis of vibration signals acquired in an underground mine. In such signals we observe seismic events which appear after the mining activity, like blasting, provoked relaxation of rock, and some unexpected events, like natural rock burst. The proposed segmentation procedures allow for extraction of such parts of the analyzed signals which are related to mentioned events.

  15. Gap Acceptance Behavior Model for Non-signalized

    OpenAIRE

    Fajaruddin Bin Mustakim

    2015-01-01

    The paper proposes field studies that were performed to determine the critical gap on the multiple rural roadways Malaysia, at non-signalized T-intersection by using The Raff and Logic Method. Critical gap between passenger car and motorcycle have been determined.   There are quite number of studied doing gap acceptance behavior model for passenger car however still few research on gap acceptance behavior model for motorcycle. Thus in this paper, logistic regression models were developed to p...

  16. Synchronous Modeling of Modular Avionics Architectures using the SIGNAL Language

    OpenAIRE

    Gamatié , Abdoulaye; Gautier , Thierry

    2002-01-01

    This document presents a study on the modeling of architecture components for avionics applications. We consider the avionics standard ARINC 653 specifications as basis, as well as the synchronous language SIGNAL to describe the modeling. A library of APEX object models (partition, process, communication and synchronization services, etc.) has been implemented. This should allow to describe distributed real-time applications using POLYCHRONY, so as to access formal tools and techniques for ar...

  17. Human reliability data collection and modelling

    International Nuclear Information System (INIS)

    1991-09-01

    The main purpose of this document is to review and outline the current state-of-the-art of the Human Reliability Assessment (HRA) used for quantitative assessment of nuclear power plants safe and economical operation. Another objective is to consider Human Performance Indicators (HPI) which can alert plant manager and regulator to departures from states of normal and acceptable operation. These two objectives are met in the three sections of this report. The first objective has been divided into two areas, based on the location of the human actions being considered. That is, the modelling and data collection associated with control room actions are addressed first in chapter 1 while actions outside the control room (including maintenance) are addressed in chapter 2. Both chapters 1 and 2 present a brief outline of the current status of HRA for these areas, and major outstanding issues. Chapter 3 discusses HPI. Such performance indicators can signal, at various levels, changes in factors which influence human performance. The final section of this report consists of papers presented by the participants of the Technical Committee Meeting. A separate abstract was prepared for each of these papers. Refs, figs and tabs

  18. Reference analysis of the signal + background model in counting experiments

    Science.gov (United States)

    Casadei, D.

    2012-01-01

    The model representing two independent Poisson processes, labelled as ``signal'' and ``background'' and both contributing additively to the total number of counted events, is considered from a Bayesian point of view. This is a widely used model for the searches of rare or exotic events in presence of a background source, as for example in the searches performed by high-energy physics experiments. In the assumption of prior knowledge about the background yield, a reference prior is obtained for the signal alone and its properties are studied. Finally, the properties of the full solution, the marginal reference posterior, are illustrated with few examples.

  19. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.

    Science.gov (United States)

    Arno, Anna I; Amini-Nik, Saeid; Blit, Patrick H; Al-Shehab, Mohammed; Belo, Cassandra; Herer, Elaine; Tien, Col Homer; Jeschke, Marc G

    2014-02-24

    The prevalence of nonhealing wounds is predicted to increase due to the growing aging population. Despite the use of novel skin substitutes and wound dressings, poorly vascularized wound niches impair wound repair. Mesenchymal stem cells (MSCs) have been reported to provide paracrine signals to promote wound healing, but the effect of human Wharton's jelly-derived MSCs (WJ-MSCs) has not yet been described in human normal skin. Human WJ-MSCs and normal skin fibroblasts were isolated from donated umbilical cords and normal adult human skin. Fibroblasts were treated with WJ-MSC-conditioned medium (WJ-MSC-CM) or nonconditioned medium. Expression of genes involved in re-epithelialization (transforming growth factor-β2), neovascularization (hypoxia-inducible factor-1α) and fibroproliferation (plasminogen activator inhibitor-1) was upregulated in WJ-MSC-CM-treated fibroblasts (P≤0.05). WJ-MSC-CM enhanced normal skin fibroblast proliferation (P≤0.001) and migration (P≤0.05), and promoted wound healing in an excisional full-thickness skin murine model. Under our experimental conditions, WJ-MSCs enhanced skin wound healing in an in vivo mouse model.

  20. Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

    Science.gov (United States)

    Kishida, Kenneth T.; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R.; Laxton, Adrian W.; Tatter, Stephen B.; White, Jason P.; Ellis, Thomas L.; Phillips, Paul E. M.; Montague, P. Read

    2016-01-01

    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID:26598677

  1. Activation of the Extracellular Signal-Regulated Kinase Signaling Is Critical for Human Umbilical Cord Mesenchymal Stem Cell Osteogenic Differentiation

    Directory of Open Access Journals (Sweden)

    Chen-Shuang Li

    2016-01-01

    Full Text Available Human umbilical cord mesenchymal stem cells (hUCMSCs are recognized as candidate progenitor cells for bone regeneration. However, the mechanism of hUCMSC osteogenesis remains unclear. In this study, we revealed that mitogen-activated protein kinases (MAPKs signaling is involved in hUCMSC osteogenic differentiation in vitro. Particularly, the activation of c-Jun N-terminal kinases (JNK and p38 signaling pathways maintained a consistent level in hUCMSCs through the entire 21-day osteogenic differentiation period. At the same time, the activation of extracellular signal-regulated kinases (ERK signaling significantly increased from day 5, peaked at day 9, and declined thereafter. Moreover, gene profiling of osteogenic markers, alkaline phosphatase (ALP activity measurement, and alizarin red staining demonstrated that the application of U0126, a specific inhibitor for ERK activation, completely prohibited hUCMSC osteogenic differentiation. However, when U0126 was removed from the culture at day 9, ERK activation and osteogenic differentiation of hUCMSCs were partially recovered. Together, these findings demonstrate that the activation of ERK signaling is essential for hUCMSC osteogenic differentiation, which points out the significance of ERK signaling pathway to regulate the osteogenic differentiation of hUCMSCs as an alternative cell source for bone tissue engineering.

  2. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    sensitivity in type I muscle fibers possibly reflects a superior effect of insulin on metabolic signaling compared to type II muscle fibers. This was investigated in the present thesis by examining muscle biopsies from lean and obese healthy subjects as well as patients with type 2 diabetes. From these muscle...

  3. Combinatorial MAPLE gradient thin film assemblies signalling to human osteoblasts

    International Nuclear Information System (INIS)

    Axente, Emanuel; Sima, Felix; Elena Sima, Livia; Serban, Natalia; Ristoscu, Carmen; Mihailescu, Ion N; Erginer, Merve; Toksoy Oner, Ebru; Eroglu, Mehmet S; Petrescu, Stefana M

    2014-01-01

    There is increased interest in smart bioactive materials to control tissue regeneration for the engineering of cell instructive scaffolds. We introduced combinatorial matrix-assisted pulsed laser evaporation (C-MAPLE) as a new method for the fabrication of organic thin films with a compositional gradient. Synchronized C-MAPLE of levan and oxidized levan was employed to assemble a two-compound biopolymer film structure. The gradient of the film composition was validated by fluorescence microscopy. In this study, we investigated the cell response induced by the compositional gradient using imaging of early osteoblast attachment and analysis of signalling phosphoprotein expression. Cells attached along the gradient in direct proportion to oxidized levan concentration. During this process distinct areas of the binary gradient have been shown to modulate the osteoblasts’ extracellular signal-regulated kinase signalling with different propensity. The proposed fabrication method results in the preparation of a new bioactive material, which could control the cell signalling response. This approach can be extended to screen new bioactive interfaces for tissue regeneration. (papers)

  4. Mathematical models of human behavior

    DEFF Research Database (Denmark)

    Møllgaard, Anders Edsberg

    at the Technical University of Denmark. The data set includes face-to-face interaction (Bluetooth), communication (calls and texts), mobility (GPS), social network (Facebook), and general background information including a psychological profile (questionnaire). This thesis presents my work on the Social Fabric...... data set, along with work on other behavioral data. The overall goal is to contribute to a quantitative understanding of human behavior using big data and mathematical models. Central to the thesis is the determination of the predictability of different human activities. Upper limits are derived....... Evidence is provided, which implies that the asymmetry is caused by a self-enhancement in the initiation dynamics. These results have implications for the formation of social networks and the dynamics of the links. It is shown that the Big Five Inventory (BFI) representing a psychological profile only...

  5. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  6. Human Thermal Model Evaluation Using the JSC Human Thermal Database

    Science.gov (United States)

    Bue, Grant; Makinen, Janice; Cognata, Thomas

    2012-01-01

    Human thermal modeling has considerable long term utility to human space flight. Such models provide a tool to predict crew survivability in support of vehicle design and to evaluate crew response in untested space environments. It is to the benefit of any such model not only to collect relevant experimental data to correlate it against, but also to maintain an experimental standard or benchmark for future development in a readily and rapidly searchable and software accessible format. The Human thermal database project is intended to do just so; to collect relevant data from literature and experimentation and to store the data in a database structure for immediate and future use as a benchmark to judge human thermal models against, in identifying model strengths and weakness, to support model development and improve correlation, and to statistically quantify a model s predictive quality. The human thermal database developed at the Johnson Space Center (JSC) is intended to evaluate a set of widely used human thermal models. This set includes the Wissler human thermal model, a model that has been widely used to predict the human thermoregulatory response to a variety of cold and hot environments. These models are statistically compared to the current database, which contains experiments of human subjects primarily in air from a literature survey ranging between 1953 and 2004 and from a suited experiment recently performed by the authors, for a quantitative study of relative strength and predictive quality of the models.

  7. State–time spectrum of signal transduction logic models

    International Nuclear Information System (INIS)

    MacNamara, Aidan; Terfve, Camille; Henriques, David; Bernabé, Beatriz Peñalver; Saez-Rodriguez, Julio

    2012-01-01

    Despite the current wealth of high-throughput data, our understanding of signal transduction is still incomplete. Mathematical modeling can be a tool to gain an insight into such processes. Detailed biochemical modeling provides deep understanding, but does not scale well above relatively a few proteins. In contrast, logic modeling can be used where the biochemical knowledge of the system is sparse and, because it is parameter free (or, at most, uses relatively a few parameters), it scales well to large networks that can be derived by manual curation or retrieved from public databases. Here, we present an overview of logic modeling formalisms in the context of training logic models to data, and specifically the different approaches to modeling qualitative to quantitative data (state) and dynamics (time) of signal transduction. We use a toy model of signal transduction to illustrate how different logic formalisms (Boolean, fuzzy logic and differential equations) treat state and time. Different formalisms allow for different features of the data to be captured, at the cost of extra requirements in terms of computational power and data quality and quantity. Through this demonstration, the assumptions behind each formalism are discussed, as well as their advantages and disadvantages and possible future developments. (paper)

  8. An improved large signal model of InP HEMTs

    Science.gov (United States)

    Li, Tianhao; Li, Wenjun; Liu, Jun

    2018-05-01

    An improved large signal model for InP HEMTs is proposed in this paper. The channel current and charge model equations are constructed based on the Angelov model equations. Both the equations for channel current and gate charge models were all continuous and high order drivable, and the proposed gate charge model satisfied the charge conservation. For the strong leakage induced barrier reduction effect of InP HEMTs, the Angelov current model equations are improved. The channel current model could fit DC performance of devices. A 2 × 25 μm × 70 nm InP HEMT device is used to demonstrate the extraction and validation of the model, in which the model has predicted the DC I–V, C–V and bias related S parameters accurately. Project supported by the National Natural Science Foundation of China (No. 61331006).

  9. Analysis and logical modeling of biological signaling transduction networks

    Science.gov (United States)

    Sun, Zhongyao

    The study of network theory and its application span across a multitude of seemingly disparate fields of science and technology: computer science, biology, social science, linguistics, etc. It is the intrinsic similarities embedded in the entities and the way they interact with one another in these systems that link them together. In this dissertation, I present from both the aspect of theoretical analysis and the aspect of application three projects, which primarily focus on signal transduction networks in biology. In these projects, I assembled a network model through extensively perusing literature, performed model-based simulations and validation, analyzed network topology, and proposed a novel network measure. The application of network modeling to the system of stomatal opening in plants revealed a fundamental question about the process that has been left unanswered in decades. The novel measure of the redundancy of signal transduction networks with Boolean dynamics by calculating its maximum node-independent elementary signaling mode set accurately predicts the effect of single node knockout in such signaling processes. The three projects as an organic whole advance the understanding of a real system as well as the behavior of such network models, giving me an opportunity to take a glimpse at the dazzling facets of the immense world of network science.

  10. Regulation of Wnt signaling by nociceptive input in animal models

    Directory of Open Access Journals (Sweden)

    Shi Yuqiang

    2012-06-01

    Full Text Available Abstract Background Central sensitization-associated synaptic plasticity in the spinal cord dorsal horn (SCDH critically contributes to the development of chronic pain, but understanding of the underlying molecular pathways is still incomplete. Emerging evidence suggests that Wnt signaling plays a crucial role in regulation of synaptic plasticity. Little is known about the potential function of the Wnt signaling cascades in chronic pain development. Results Fluorescent immunostaining results indicate that β-catenin, an essential protein in the canonical Wnt signaling pathway, is expressed in the superficial layers of the mouse SCDH with enrichment at synapses in lamina II. In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers. Immunoblotting analysis indicates that both Wnt3a a β-catenin are up-regulated in the SCDH of various mouse pain models created by hind-paw injection of capsaicin, intrathecal (i.t. injection of HIV-gp120 protein or spinal nerve ligation (SNL. Furthermore, Wnt5a, a prototypic Wnt ligand for non-canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models. Conclusion Our results suggest that Wnt signaling pathways are regulated by nociceptive input. The activation of Wnt signaling may regulate the expression of spinal central sensitization during the development of acute and chronic pain.

  11. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  12. Multi-model approach to characterize human handwriting motion.

    Science.gov (United States)

    Chihi, I; Abdelkrim, A; Benrejeb, M

    2016-02-01

    This paper deals with characterization and modelling of human handwriting motion from two forearm muscle activity signals, called electromyography signals (EMG). In this work, an experimental approach was used to record the coordinates of a pen tip moving on the (x, y) plane and EMG signals during the handwriting act. The main purpose is to design a new mathematical model which characterizes this biological process. Based on a multi-model approach, this system was originally developed to generate letters and geometric forms written by different writers. A Recursive Least Squares algorithm is used to estimate the parameters of each sub-model of the multi-model basis. Simulations show good agreement between predicted results and the recorded data.

  13. Showing Off in Humans: Male Generosity as a Mating Signal

    Directory of Open Access Journals (Sweden)

    Wendy Iredale

    2008-07-01

    Full Text Available We examined people's charity contributions while in the presence of an observer of the same sex, opposite sex, or no observer. Inspired by costly signaling theory, we hypothesized that men would be more generous in the presence of a potential mate. Men and women played a number of experimental games in which they could earn money. On completion of these games participants were asked what percentage of their earned money they would be willing to donate to charity. Our results show that men contribute more to charity when observed by a member of the opposite sex than by a member of the same sex or no observer. Conversely, female charity donations did not significantly vary across the three observer conditions. Findings support the notion that men's generosity might have evolved as a mating signal.

  14. Signalling network construction for modelling plant defence response.

    Directory of Open Access Journals (Sweden)

    Dragana Miljkovic

    Full Text Available Plant defence signalling response against various pathogens, including viruses, is a complex phenomenon. In resistant interaction a plant cell perceives the pathogen signal, transduces it within the cell and performs a reprogramming of the cell metabolism leading to the pathogen replication arrest. This work focuses on signalling pathways crucial for the plant defence response, i.e., the salicylic acid, jasmonic acid and ethylene signal transduction pathways, in the Arabidopsis thaliana model plant. The initial signalling network topology was constructed manually by defining the representation formalism, encoding the information from public databases and literature, and composing a pathway diagram. The manually constructed network structure consists of 175 components and 387 reactions. In order to complement the network topology with possibly missing relations, a new approach to automated information extraction from biological literature was developed. This approach, named Bio3graph, allows for automated extraction of biological relations from the literature, resulting in a set of (component1, reaction, component2 triplets and composing a graph structure which can be visualised, compared to the manually constructed topology and examined by the experts. Using a plant defence response vocabulary of components and reaction types, Bio3graph was applied to a set of 9,586 relevant full text articles, resulting in 137 newly detected reactions between the components. Finally, the manually constructed topology and the new reactions were merged to form a network structure consisting of 175 components and 524 reactions. The resulting pathway diagram of plant defence signalling represents a valuable source for further computational modelling and interpretation of omics data. The developed Bio3graph approach, implemented as an executable language processing and graph visualisation workflow, is publically available at http://ropot.ijs.si/bio3graph/and can be

  15. Modeling, estimation and optimal filtration in signal processing

    CERN Document Server

    Najim, Mohamed

    2010-01-01

    The purpose of this book is to provide graduate students and practitioners with traditional methods and more recent results for model-based approaches in signal processing.Firstly, discrete-time linear models such as AR, MA and ARMA models, their properties and their limitations are introduced. In addition, sinusoidal models are addressed.Secondly, estimation approaches based on least squares methods and instrumental variable techniques are presented.Finally, the book deals with optimal filters, i.e. Wiener and Kalman filtering, and adaptive filters such as the RLS, the LMS and the

  16. Decoding Problem Gamblers' Signals: A Decision Model for Casino Enterprises.

    Science.gov (United States)

    Ifrim, Sandra

    2015-12-01

    The aim of the present study is to offer a validated decision model for casino enterprises. The model enables those users to perform early detection of problem gamblers and fulfill their ethical duty of social cost minimization. To this end, the interpretation of casino customers' nonverbal communication is understood as a signal-processing problem. Indicators of problem gambling recommended by Delfabbro et al. (Identifying problem gamblers in gambling venues: final report, 2007) are combined with Viterbi algorithm into an interdisciplinary model that helps decoding signals emitted by casino customers. Model output consists of a historical path of mental states and cumulated social costs associated with a particular client. Groups of problem and non-problem gamblers were simulated to investigate the model's diagnostic capability and its cost minimization ability. Each group consisted of 26 subjects and was subsequently enlarged to 100 subjects. In approximately 95% of the cases, mental states were correctly decoded for problem gamblers. Statistical analysis using planned contrasts revealed that the model is relatively robust to the suppression of signals performed by casino clientele facing gambling problems as well as to misjudgments made by staff regarding the clients' mental states. Only if the last mentioned source of error occurs in a very pronounced manner, i.e. judgment is extremely faulty, cumulated social costs might be distorted.

  17. Vicarious Learning from Human Models in Monkeys

    OpenAIRE

    Falcone, Rossella; Brunamonti, Emiliano; Genovesio, Aldo

    2012-01-01

    We examined whether monkeys can learn by observing a human model, through vicarious learning. Two monkeys observed a human model demonstrating an object-reward association and consuming food found underneath an object. The monkeys observed human models as they solved more than 30 learning problems. For each problem, the human models made a choice between two objects, one of which concealed a piece of apple. In the test phase afterwards, the monkeys made a choice of their own. Learning was app...

  18. Electrical signal analysis to assess the physical condition of a human or animal

    Science.gov (United States)

    Cox, Daryl F.; Hochanadel, Charles D.; Haynes, Howard D.

    2010-06-15

    The invention is a human and animal performance data acquisition, analysis, and diagnostic system for fitness and therapy devices having an interface box removably disposed on incoming power wiring to a fitness and therapy device, at least one current transducer removably disposed on said interface box for sensing current signals to said fitness and therapy device, and a means for analyzing, displaying, and reporting said current signals to determine human and animal performance on said device using measurable parameters.

  19. Membrane-associated signaling in human B-lymphoma lines

    Energy Technology Data Exchange (ETDEWEB)

    Tauzin, Sebastien; Ding, Heidrun; Burdevet, Dimitri [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Borisch, Bettina [Department of Social and Preventive Medicine, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Hoessli, Daniel C., E-mail: danielhoessli@gmail.com [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland)

    2011-01-15

    In B-non-Hodgkin lymphomas, Lyn and Cbp/PAG constitute the core of an oncogenic signalosome that captures the Phosphatidylinositol-3-kinase, the Spleen tyrosine kinase and the Signal transducer and activator of transcription-3 to generate pro-survival and proliferative signals. Lymphoma lines corresponding to follicular, mantle-cell and Burkitt-derived lymphomas display type-specific signalosome organizations that differentially activate PI3K, Syk and STAT3. In the follicular lymphoma line, PI3K, Syk and STAT3 were optimally activated upon association with the Lyn-Cbp/PAG signalosome, while in the Burkitt lymphoma-derived line, the association with Cbp/PAG and activation of PI3K were interfered with by the latent membrane proteins encoded by the Epstein-Barr virus. In the Jeko-1 mantle-cell line, a weak association of Syk with the Lyn-Cbp/PAG signalosome resulted in poor activation of Syk, but in those cells, as in the follicular and Burkitt-derived lines, efficient apoptosis induction by the Syk inhibitor R406 indicated that Syk is nonetheless an important prosurvival element and therefore a valuable therapeutic target. In all configurations described herein is the Lyn-Cbp/PAG signalosome independent of external signals and provides efficient means of activation for its associated lipid and protein kinases. In follicular and Burkitt-derived lines, Syk appears to be activated following binding to Cbp/PAG and no longer requires B-cell receptor-associated activation motifs for activation. Assessment of the different modalities of Lyn-Cbp/PAG signalosome organization could help in selecting the appropriate combination of kinase inhibitors to eliminate a particular type of lymphoma cells.

  20. Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition

    Directory of Open Access Journals (Sweden)

    Ramkumar Menon

    2017-08-01

    Full Text Available Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species—indicative of different phylogenetic clocks and alarms—but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen-activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system.

  1. D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

    Science.gov (United States)

    Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

    2011-02-14

    Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Development of BOLD signal hemodynamic responses in the human brain

    NARCIS (Netherlands)

    Arichi, T.; Varela, M.; Melendez-Calderon, A.; Allievi, A.; Merchant, N.; Tusor, N.; Counsell, S.J.; Burdet, E.; Beckmann, Christian; Edwards, A.D.

    2012-01-01

    In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing

  3. Envelope statistics of self-motion signals experienced by human subjects during everyday activities: Implications for vestibular processing.

    Science.gov (United States)

    Carriot, Jérome; Jamali, Mohsen; Cullen, Kathleen E; Chacron, Maurice J

    2017-01-01

    There is accumulating evidence that the brain's neural coding strategies are constrained by natural stimulus statistics. Here we investigated the statistics of the time varying envelope (i.e. a second-order stimulus attribute that is related to variance) of rotational and translational self-motion signals experienced by human subjects during everyday activities. We found that envelopes can reach large values across all six motion dimensions (~450 deg/s for rotations and ~4 G for translations). Unlike results obtained in other sensory modalities, the spectral power of envelope signals decreased slowly for low (2 Hz) temporal frequencies and thus was not well-fit by a power law. We next compared the spectral properties of envelope signals resulting from active and passive self-motion, as well as those resulting from signals obtained when the subject is absent (i.e. external stimuli). Our data suggest that different mechanisms underlie deviation from scale invariance in rotational and translational self-motion envelopes. Specifically, active self-motion and filtering by the human body cause deviation from scale invariance primarily for translational and rotational envelope signals, respectively. Finally, we used well-established models in order to predict the responses of peripheral vestibular afferents to natural envelope stimuli. We found that irregular afferents responded more strongly to envelopes than their regular counterparts. Our findings have important consequences for understanding the coding strategies used by the vestibular system to process natural second-order self-motion signals.

  4. Experimental investigation of the cytotoxicity of medium-borne signals in human prostate cancer cell line

    International Nuclear Information System (INIS)

    Sjostedt, Svetlana; Bezak, Eva

    2012-01-01

    Introduction. Evidence exists that exposure of non-irradiated cells to Irradiated Cell Conditioned Medium (ICCM) can cause effects similar to those resulting from direct radiation damage. This study attempts to validate the stochastic model, relating absorbed dose to the emission and processing of cell death signals by non-irradiated cells, in vitro in PC3 human prostate cancer cell line. Methods. The recipient cell survival was measured after exposure of cells to ICMM derived from donor cells: a) exposed to radiation doses from 2 Gy to 8 Gy and b) of concentrations varying from 2 x 10 2 to 6 x 10 6 irradiated with 2 Gy. Results. Exposure to ICCM, irradiated with doses between 2-8 Gy, resulted in a significant (p 2 cells was significantly higher (p < 0.5) compared to the rest of donor cell concentrations, indicating that the toxicity of ICCM depends on the cellular concentration of donor cells. Non-linear regression data fitting provided reasonable agreement with the microdosimetric model for the induction of cell killing through medium-borne signals. Conclusion. For the given cell line and given experimental conditions, significant decreases in cell survival were observed in non-irradiated cells exposed to ICCM derived from donor cells of various concentrations and irradiated with different doses

  5. Vicarious learning from human models in monkeys.

    Science.gov (United States)

    Falcone, Rossella; Brunamonti, Emiliano; Genovesio, Aldo

    2012-01-01

    We examined whether monkeys can learn by observing a human model, through vicarious learning. Two monkeys observed a human model demonstrating an object-reward association and consuming food found underneath an object. The monkeys observed human models as they solved more than 30 learning problems. For each problem, the human models made a choice between two objects, one of which concealed a piece of apple. In the test phase afterwards, the monkeys made a choice of their own. Learning was apparent from the first trial of the test phase, confirming the ability of monkeys to learn by vicarious observation of human models.

  6. Vicarious learning from human models in monkeys.

    Directory of Open Access Journals (Sweden)

    Rossella Falcone

    Full Text Available We examined whether monkeys can learn by observing a human model, through vicarious learning. Two monkeys observed a human model demonstrating an object-reward association and consuming food found underneath an object. The monkeys observed human models as they solved more than 30 learning problems. For each problem, the human models made a choice between two objects, one of which concealed a piece of apple. In the test phase afterwards, the monkeys made a choice of their own. Learning was apparent from the first trial of the test phase, confirming the ability of monkeys to learn by vicarious observation of human models.

  7. Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

    Directory of Open Access Journals (Sweden)

    Venkatachalem Sathish

    2015-06-01

    Full Text Available Aims: Cigarette smoke (CS in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective bronchodilatory role of estrogens, thus worsening airway contractility. Methods: We tested effects of cigarette smoke extract (CSE on 17β-estradiol (E2 signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM obtained from lung samples of non-smoking female patients undergoing thoracic surgery. Results: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca2+]i responses to 10µM histamine. Acute exposure to physiological concentrations of E2 decreased [Ca2+]i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E2 on [Ca2+]i was blunted. Acute E2 exposure also decreased store-operated Ca2+ entry and inhibited stromal interaction molecule 1 (STIM1 phosphorylation: effects blunted by CSE. Acute exposure to E2 increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERα. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E2 compared to non-CSE controls. Conclusion: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

  8. Human Performance Modeling for Dynamic Human Reliability Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Boring, Ronald Laurids [Idaho National Laboratory; Joe, Jeffrey Clark [Idaho National Laboratory; Mandelli, Diego [Idaho National Laboratory

    2015-08-01

    Part of the U.S. Department of Energy’s (DOE’s) Light Water Reac- tor Sustainability (LWRS) Program, the Risk-Informed Safety Margin Charac- terization (RISMC) Pathway develops approaches to estimating and managing safety margins. RISMC simulations pair deterministic plant physics models with probabilistic risk models. As human interactions are an essential element of plant risk, it is necessary to integrate human actions into the RISMC risk framework. In this paper, we review simulation based and non simulation based human reliability analysis (HRA) methods. This paper summarizes the founda- tional information needed to develop a feasible approach to modeling human in- teractions in RISMC simulations.

  9. Smart driver monitoring : when signal processing meets human factors : in the driver's seat

    NARCIS (Netherlands)

    Aghaei, A.S.; Donmez, B.; Liu, C.C.; He, D.; Liu, G.; Plataniotis, K.N.; Chen, H.Y.W.; Sojoudi, Z.

    2016-01-01

    This article provides an interdisciplinary perspective on driver monitoring systems by discussing state-of-the-art signal processing solutions in the context of road safety issues identified in human factors research. Recently, the human factors community has made significant progress in

  10. Dynamic Bayesian Network Modeling of the Interplay between EGFR and Hedgehog Signaling.

    Science.gov (United States)

    Fröhlich, Holger; Bahamondez, Gloria; Götschel, Frank; Korf, Ulrike

    2015-01-01

    Aberrant activation of sonic Hegdehog (SHH) signaling has been found to disrupt cellular differentiation in many human cancers and to increase proliferation. The SHH pathway is known to cross-talk with EGFR dependent signaling. Recent studies experimentally addressed this interplay in Daoy cells, which are presumable a model system for medulloblastoma, a highly malignant brain tumor that predominately occurs in children. Currently ongoing are several clinical trials for different solid cancers, which are designed to validate the clinical benefits of targeting the SHH in combination with other pathways. This has motivated us to investigate interactions between EGFR and SHH dependent signaling in greater depth. To our knowledge, there is no mathematical model describing the interplay between EGFR and SHH dependent signaling in medulloblastoma so far. Here we come up with a fully probabilistic approach using Dynamic Bayesian Networks (DBNs). To build our model, we made use of literature based knowledge describing SHH and EGFR signaling and integrated gene expression (Illumina) and cellular location dependent time series protein expression data (Reverse Phase Protein Arrays). We validated our model by sub-sampling training data and making Bayesian predictions on the left out test data. Our predictions focusing on key transcription factors and p70S6K, showed a high level of concordance with experimental data. Furthermore, the stability of our model was tested by a parametric bootstrap approach. Stable network features were in agreement with published data. Altogether we believe that our model improved our understanding of the interplay between two highly oncogenic signaling pathways in Daoy cells. This may open new perspectives for the future therapy of Hedghog/EGF-dependent solid tumors.

  11. Nonlinear signal processing using neural networks: Prediction and system modelling

    Energy Technology Data Exchange (ETDEWEB)

    Lapedes, A.; Farber, R.

    1987-06-01

    The backpropagation learning algorithm for neural networks is developed into a formalism for nonlinear signal processing. We illustrate the method by selecting two common topics in signal processing, prediction and system modelling, and show that nonlinear applications can be handled extremely well by using neural networks. The formalism is a natural, nonlinear extension of the linear Least Mean Squares algorithm commonly used in adaptive signal processing. Simulations are presented that document the additional performance achieved by using nonlinear neural networks. First, we demonstrate that the formalism may be used to predict points in a highly chaotic time series with orders of magnitude increase in accuracy over conventional methods including the Linear Predictive Method and the Gabor-Volterra-Weiner Polynomial Method. Deterministic chaos is thought to be involved in many physical situations including the onset of turbulence in fluids, chemical reactions and plasma physics. Secondly, we demonstrate the use of the formalism in nonlinear system modelling by providing a graphic example in which it is clear that the neural network has accurately modelled the nonlinear transfer function. It is interesting to note that the formalism provides explicit, analytic, global, approximations to the nonlinear maps underlying the various time series. Furthermore, the neural net seems to be extremely parsimonious in its requirements for data points from the time series. We show that the neural net is able to perform well because it globally approximates the relevant maps by performing a kind of generalized mode decomposition of the maps. 24 refs., 13 figs.

  12. Acoustic/seismic signal propagation and sensor performance modeling

    Science.gov (United States)

    Wilson, D. Keith; Marlin, David H.; Mackay, Sean

    2007-04-01

    Performance, optimal employment, and interpretation of data from acoustic and seismic sensors depend strongly and in complex ways on the environment in which they operate. Software tools for guiding non-expert users of acoustic and seismic sensors are therefore much needed. However, such tools require that many individual components be constructed and correctly connected together. These components include the source signature and directionality, representation of the atmospheric and terrain environment, calculation of the signal propagation, characterization of the sensor response, and mimicking of the data processing at the sensor. Selection of an appropriate signal propagation model is particularly important, as there are significant trade-offs between output fidelity and computation speed. Attenuation of signal energy, random fading, and (for array systems) variations in wavefront angle-of-arrival should all be considered. Characterization of the complex operational environment is often the weak link in sensor modeling: important issues for acoustic and seismic modeling activities include the temporal/spatial resolution of the atmospheric data, knowledge of the surface and subsurface terrain properties, and representation of ambient background noise and vibrations. Design of software tools that address these challenges is illustrated with two examples: a detailed target-to-sensor calculation application called the Sensor Performance Evaluator for Battlefield Environments (SPEBE) and a GIS-embedded approach called Battlefield Terrain Reasoning and Awareness (BTRA).

  13. MOTORCYCLE CRASH PREDICTION MODEL FOR NON-SIGNALIZED INTERSECTIONS

    Directory of Open Access Journals (Sweden)

    S. HARNEN

    2003-01-01

    Full Text Available This paper attempts to develop a prediction model for motorcycle crashes at non-signalized intersections on urban roads in Malaysia. The Generalized Linear Modeling approach was used to develop the model. The final model revealed that an increase in motorcycle and non-motorcycle flows entering an intersection is associated with an increase in motorcycle crashes. Non-motorcycle flow on major road had the greatest effect on the probability of motorcycle crashes. Approach speed, lane width, number of lanes, shoulder width and land use were also found to be significant in explaining motorcycle crashes. The model should assist traffic engineers to decide the need for appropriate intersection treatment that specifically designed for non-exclusive motorcycle lane facilities.

  14. Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms.

    Science.gov (United States)

    Marei, Hadir; Malliri, Angeliki

    2017-07-03

    Abnormal Rac1 signaling is linked to a number of debilitating human diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. As such, Rac1 represents an attractive therapeutic target, yet the search for effective Rac1 inhibitors is still underway. Given the adverse effects associated with Rac1 signaling perturbation, cells have evolved several mechanisms to ensure the tight regulation of Rac1 signaling. Thus, characterizing these mechanisms can provide invaluable information regarding major cellular events that lead to aberrant Rac1 signaling. Importantly, this information can be utilized to further facilitate the development of effective pharmacological modulators that can restore normal Rac1 signaling. In this review, we focus on the pathological role of Rac1 signaling, highlighting the benefits and potential drawbacks of targeting Rac1 in a clinical setting. Additionally, we provide an overview of available compounds that target key Rac1 regulatory mechanisms and discuss future therapeutic avenues arising from our understanding of these mechanisms.

  15. Human-machine interface based on muscular and brain signals applied to a robotic wheelchair

    International Nuclear Information System (INIS)

    Ferreira, A; Silva, R L; Celeste, W C; Filho, T F Bastos; Filho, M Sarcinelli

    2007-01-01

    This paper presents a Human-Machine Interface (HMI) based on the signals generated by eye blinks or brain activity. The system structure and the signal acquisition and processing are shown. The signals used in this work are either the signal associated to the muscular movement corresponding to an eye blink or the brain signal corresponding to visual information processing. The variance is the feature extracted from such signals in order to detect the intention of the user. The classification is performed by a variance threshold which is experimentally determined for each user during the training stage. The command options, which are going to be sent to the commanded device, are presented to the user in the screen of a PDA (Personal Digital Assistant). In the experiments here reported, a robotic wheelchair is used as the device being commanded

  16. Human-machine interface based on muscular and brain signals applied to a robotic wheelchair

    Energy Technology Data Exchange (ETDEWEB)

    Ferreira, A; Silva, R L; Celeste, W C; Filho, T F Bastos; Filho, M Sarcinelli [Electrical Engineering Department, Federal University of Espirito Santo (UFES), Av. Fernando Ferrari, 514, Vitoria, 29075-910 (Brazil)

    2007-11-15

    This paper presents a Human-Machine Interface (HMI) based on the signals generated by eye blinks or brain activity. The system structure and the signal acquisition and processing are shown. The signals used in this work are either the signal associated to the muscular movement corresponding to an eye blink or the brain signal corresponding to visual information processing. The variance is the feature extracted from such signals in order to detect the intention of the user. The classification is performed by a variance threshold which is experimentally determined for each user during the training stage. The command options, which are going to be sent to the commanded device, are presented to the user in the screen of a PDA (Personal Digital Assistant). In the experiments here reported, a robotic wheelchair is used as the device being commanded.

  17. Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota

    DEFF Research Database (Denmark)

    Wahlström, Annika; Kovatcheva-Datchary, Petia; Ståhlman, Marcus

    2017-01-01

    The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR...... signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum...... and liver. We found that cecal microbiota composition differed between mice colonized with mouse and human microbiota and was stable over time. Human and mouse microbiota reduced total BA levels similarly, but the humanized mice produced less secondary BAs. The human microbiota was able to reduce the levels...

  18. Different Signal Enhancement Pathways of Attention and Consciousness Underlie Perception in Humans.

    Science.gov (United States)

    van Boxtel, Jeroen J A

    2017-06-14

    It is not yet known whether attention and consciousness operate through similar or largely different mechanisms. Visual processing mechanisms are routinely characterized by measuring contrast response functions (CRFs). In this report, behavioral CRFs were obtained in humans (both males and females) by measuring afterimage durations over the entire range of inducer stimulus contrasts to reveal visual mechanisms behind attention and consciousness. Deviations relative to the standard CRF, i.e., gain functions, describe the strength of signal enhancement, which were assessed for both changes due to attentional task and conscious perception. It was found that attention displayed a response-gain function, whereas consciousness displayed a contrast-gain function. Through model comparisons, which only included contrast-gain modulations, both contrast-gain and response-gain effects can be explained with a two-level normalization model, in which consciousness affects only the first level and attention affects only the second level. These results demonstrate that attention and consciousness can effectively show different gain functions because they operate through different signal enhancement mechanisms. SIGNIFICANCE STATEMENT The relationship between attention and consciousness is still debated. Mapping contrast response functions (CRFs) has allowed (neuro)scientists to gain important insights into the mechanistic underpinnings of visual processing. Here, the influence of both attention and consciousness on these functions were measured and they displayed a strong dissociation. First, attention lowered CRFs, whereas consciousness raised them. Second, attention manifests itself as a response-gain function, whereas consciousness manifests itself as a contrast-gain function. Extensive model comparisons show that these results are best explained in a two-level normalization model in which consciousness affects only the first level, whereas attention affects only the second level

  19. Neuropeptidomics Mass Spectrometry Reveals Signaling Networks Generated by Distinct Protease Pathways in Human Systems

    Science.gov (United States)

    Hook, Vivian; Bandeira, Nuno

    2015-12-01

    Neuropeptides regulate intercellular signaling as neurotransmitters of the central and peripheral nervous systems, and as peptide hormones in the endocrine system. Diverse neuropeptides of distinct primary sequences of various lengths, often with post-translational modifications, coordinate and integrate regulation of physiological functions. Mass spectrometry-based analysis of the diverse neuropeptide structures in neuropeptidomics research is necessary to define the full complement of neuropeptide signaling molecules. Human neuropeptidomics has notable importance in defining normal and dysfunctional neuropeptide signaling in human health and disease. Neuropeptidomics has great potential for expansion in translational research opportunities for defining neuropeptide mechanisms of human diseases, providing novel neuropeptide drug targets for drug discovery, and monitoring neuropeptides as biomarkers of drug responses. In consideration of the high impact of human neuropeptidomics for health, an observed gap in this discipline is the few published articles in human neuropeptidomics compared with, for example, human proteomics and related mass spectrometry disciplines. Focus on human neuropeptidomics will advance new knowledge of the complex neuropeptide signaling networks participating in the fine control of neuroendocrine systems. This commentary review article discusses several human neuropeptidomics accomplishments that illustrate the rapidly expanding diversity of neuropeptides generated by protease processing of pro-neuropeptide precursors occurring within the secretory vesicle proteome. Of particular interest is the finding that human-specific cathepsin V participates in producing enkephalin and likely other neuropeptides, indicating unique proteolytic mechanisms for generating human neuropeptides. The field of human neuropeptidomics has great promise to solve new mechanisms in disease conditions, leading to new drug targets and therapeutic agents for human

  20. Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways.

    Science.gov (United States)

    Shenk, Thomas; Alwine, James C

    2014-11-01

    Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.

  1. The amino-terminal domain of human signal transducers and ...

    Indian Academy of Sciences (India)

    Unknown

    transferase (GST) moiety was cloned into the expression vector pGEX-2T ... containing 100 µg/ml of ampicillin to mid log phase as indicated by the .... equipped with pulsed field gradients. ... ferent algorithms like hidden Markov model (HMM).

  2. Pearls and pitfalls in human pharmacological models of migraine

    DEFF Research Database (Denmark)

    Ashina, Messoud; Hansen, Jakob Møller; Olesen, Jes

    2013-01-01

    In vitro studies have contributed to the characterization of receptors in cranial blood vessels and the identification of new possible anti-migraine agents. In vivo animal models enable the study of vascular responses, neurogenic inflammation, peptide release and genetic predisposition and thus......- or migraine-provoking property of naturally occurring signaling molecules can be tested in a human model. If such an endogenous substance can provoke migraine in human patients, then it is likely, although not certain, that blocking its effect will be effective in the treatment of acute migraine attacks...... an important role in translational migraine research leading to the identification of three new principally different targets in the treatment of acute migraine attacks and has been used to examine other endogenous signaling molecules as well as genetic susceptibility factors. New additions to the model...

  3. Modeling Guidelines for Code Generation in the Railway Signaling Context

    Science.gov (United States)

    Ferrari, Alessio; Bacherini, Stefano; Fantechi, Alessandro; Zingoni, Niccolo

    2009-01-01

    Modeling guidelines constitute one of the fundamental cornerstones for Model Based Development. Their relevance is essential when dealing with code generation in the safety-critical domain. This article presents the experience of a railway signaling systems manufacturer on this issue. Introduction of Model-Based Development (MBD) and code generation in the industrial safety-critical sector created a crucial paradigm shift in the development process of dependable systems. While traditional software development focuses on the code, with MBD practices the focus shifts to model abstractions. The change has fundamental implications for safety-critical systems, which still need to guarantee a high degree of confidence also at code level. Usage of the Simulink/Stateflow platform for modeling, which is a de facto standard in control software development, does not ensure by itself production of high-quality dependable code. This issue has been addressed by companies through the definition of modeling rules imposing restrictions on the usage of design tools components, in order to enable production of qualified code. The MAAB Control Algorithm Modeling Guidelines (MathWorks Automotive Advisory Board)[3] is a well established set of publicly available rules for modeling with Simulink/Stateflow. This set of recommendations has been developed by a group of OEMs and suppliers of the automotive sector with the objective of enforcing and easing the usage of the MathWorks tools within the automotive industry. The guidelines have been published in 2001 and afterwords revisited in 2007 in order to integrate some additional rules developed by the Japanese division of MAAB [5]. The scope of the current edition of the guidelines ranges from model maintainability and readability to code generation issues. The rules are conceived as a reference baseline and therefore they need to be tailored to comply with the characteristics of each industrial context. Customization of these

  4. Modeling SMAP Spacecraft Attitude Control Estimation Error Using Signal Generation Model

    Science.gov (United States)

    Rizvi, Farheen

    2016-01-01

    Two ground simulation software are used to model the SMAP spacecraft dynamics. The CAST software uses a higher fidelity model than the ADAMS software. The ADAMS software models the spacecraft plant, controller and actuator models, and assumes a perfect sensor and estimator model. In this simulation study, the spacecraft dynamics results from the ADAMS software are used as CAST software is unavailable. The main source of spacecraft dynamics error in the higher fidelity CAST software is due to the estimation error. A signal generation model is developed to capture the effect of this estimation error in the overall spacecraft dynamics. Then, this signal generation model is included in the ADAMS software spacecraft dynamics estimate such that the results are similar to CAST. This signal generation model has similar characteristics mean, variance and power spectral density as the true CAST estimation error. In this way, ADAMS software can still be used while capturing the higher fidelity spacecraft dynamics modeling from CAST software.

  5. A Segmented Signal Progression Model for the Modern Streetcar System

    Directory of Open Access Journals (Sweden)

    Baojie Wang

    2015-01-01

    Full Text Available This paper is on the purpose of developing a segmented signal progression model for modern streetcar system. The new method is presented with the following features: (1 the control concept is based on the assumption of only one streetcar line operating along an arterial under a constant headway and no bandwidth demand for streetcar system signal progression; (2 the control unit is defined as a coordinated intersection group associated with several streetcar stations, and the control joints must be streetcar stations; (3 the objective function is built to ensure the two-way streetcar arrival times distributing within the available time of streetcar phase; (4 the available time of streetcar phase is determined by timing schemes, intersection structures, track locations, streetcar speeds, and vehicular accelerations; (5 the streetcar running speed is constant separately whether it is in upstream or downstream route; (6 the streetcar dwell time is preset according to historical data distribution or charging demand. The proposed method is experimentally examined in Hexi New City Streetcar Project in Nanjing, China. In the experimental results, the streetcar system operation and the progression impacts are shown to affect transit and vehicular traffic. The proposed model presents promising outcomes through the design of streetcar system segmented signal progression, in terms of ensuring high streetcar system efficiency and minimizing negative impacts on transit and vehicular traffic.

  6. Modeling skull's acoustic attenuation and dispersion on photoacoustic signal

    Science.gov (United States)

    Mohammadi, L.; Behnam, H.; Nasiriavanaki, M. R.

    2017-03-01

    Despite the great promising results of a recent new transcranial photoacoustic brain imaging technology, it has been shown that the presence of the skull severely affects the performance of this imaging modality. In this paper, we investigate the effect of skull on generated photoacoustic signals with a mathematical model. The developed model takes into account the frequency dependence attenuation and acoustic dispersion effects occur with the wave reflection and refraction at the skull surface. Numerical simulations based on the developed model are performed for calculating the propagation of photoacoustic waves through the skull. From the simulation results, it was found that the skull-induced distortion becomes very important and the reconstructed image would be strongly distorted without correcting these effects. In this regard, it is anticipated that an accurate quantification and modeling of the skull transmission effects would ultimately allow for skull aberration correction in transcranial photoacoustic brain imaging.

  7. Mathematical modeling of gonadotropin-releasing hormone signaling.

    Science.gov (United States)

    Pratap, Amitesh; Garner, Kathryn L; Voliotis, Margaritis; Tsaneva-Atanasova, Krasimira; McArdle, Craig A

    2017-07-05

    Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes to control reproduction. These are G q -coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the chronic regulation of their synthesis. GnRH is secreted in short pulses and GnRH effects on its target cells are dependent upon the dynamics of these pulses. Here we overview GnRH receptors and their signaling network, placing emphasis on pulsatile signaling, and how mechanistic mathematical models and an information theoretic approach have helped further this field. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Purkinje Cell Signaling Deficits in Animal Models of Ataxia

    Directory of Open Access Journals (Sweden)

    Eriola Hoxha

    2018-04-01

    Full Text Available Purkinje cell (PC dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction. Mutations affecting Na+ channels (NaV1.1, NaV1.6, NaVβ4, Fgf14 or Rer1 reduce the firing rate of PCs, mainly via an impairment of the Na+ resurgent current. Mutations that reduce Kv3 currents limit the firing rate frequency range. Mutations of Kv1 channels act mainly on inhibitory interneurons, generating excessive GABAergic signaling onto PCs, resulting in episodic ataxia. Kv4.3 mutations are responsible for a complex syndrome with several neurologic dysfunctions including ataxia. Mutations of either Cav or BK channels have similar consequences, consisting in a disruption of the firing pattern of PCs, with loss of precision, leading to ataxia. Another category of pathogenic mechanisms of ataxia regards alterations of synaptic signals arriving at the PC. At the parallel fiber (PF-PC synapse, mutations of glutamate delta-2 (GluD2 or its ligand Crbl1 are responsible for the loss of synaptic contacts, abolishment of long-term depression (LTD and motor deficits. At the same synapse, a correct function of metabotropic glutamate receptor 1 (mGlu1 receptors is necessary to avoid ataxia. Failure of climbing fiber (CF maturation and establishment of PC mono-innervation occurs in a great number of mutant mice, including mGlu1 and its transduction pathway, GluD2, semaphorins and their receptors. All these models have in common the alteration of PC output signals, due to a variety of mechanisms affecting incoming

  9. Skull's acoustic attenuation and dispersion modeling on photoacoustic signal

    Science.gov (United States)

    Mohammadi, Leila; Behnam, Hamid; Tavakkoli, Jahan; Nasiriavanaki, Mohammadreza

    2018-02-01

    Despite the promising results of the recent novel transcranial photoacoustic (PA) brain imaging technology, it has been demonstrated that the presence of the skull severely affects the performance of this imaging modality. We theoretically investigate the effects of acoustic heterogeneity induced by skull on the PA signals generated from single particles, with firstly developing a mathematical model for this phenomenon and then explore experimental validation of the results. The model takes into account the frequency dependent attenuation and dispersion effects occur with wave reflection, refraction and mode conversion at the skull surfaces. Numerical simulations based on the developed model are performed for calculating the propagation of photoacoustic waves through the skull. The results show a strong agreement between simulation and ex-vivo study. The findings are as follow: The thickness of the skull is the most PA signal deteriorating factor that affects both its amplitude (attenuation) and phase (distortion). Also we demonstrated that, when the depth of target region is low and it is comparable to the skull thickness, however, the skull-induced distortion becomes increasingly severe and the reconstructed image would be strongly distorted without correcting these effects. It is anticipated that an accurate quantification and modeling of the skull transmission effects would ultimately allow for aberration correction in transcranial PA brain imaging.

  10. Adaptive control of human action: The role of outcome representations and reward signals

    Directory of Open Access Journals (Sweden)

    Hans eMarien

    2013-09-01

    Full Text Available The present paper aims to advance the understanding of the control of human behavior by integrating two lines of literature that so far have led separate lives. First, one line of literature is concerned with the ideomotor principle of human behavior, according to which actions are represented in terms of their outcomes. The second line of literature mainly considers the role of reward signals in adaptive control. Here, we offer a combined perspective on how outcome representations and reward signals work together to modulate adaptive control processes. We propose that reward signals signify the value of outcome representations and facilitate the recruitment of control resources in situations where behavior needs to be maintained or adapted to attain the represented outcome. We discuss recent research demonstrating how adaptive control of goal-directed behavior may emerge when outcome representations are co-activated with positive reward signals.

  11. Performance analysis of NOAA tropospheric signal delay model

    International Nuclear Information System (INIS)

    Ibrahim, Hassan E; El-Rabbany, Ahmed

    2011-01-01

    Tropospheric delay is one of the dominant global positioning system (GPS) errors, which degrades the positioning accuracy. Recent development in tropospheric modeling relies on implementation of more accurate numerical weather prediction (NWP) models. In North America one of the NWP-based tropospheric correction models is the NOAA Tropospheric Signal Delay Model (NOAATrop), which was developed by the US National Oceanic and Atmospheric Administration (NOAA). Because of its potential to improve the GPS positioning accuracy, the NOAATrop model became the focus of many researchers. In this paper, we analyzed the performance of the NOAATrop model and examined its effect on ionosphere-free-based precise point positioning (PPP) solution. We generated 3 year long tropospheric zenith total delay (ZTD) data series for the NOAATrop model, Hopfield model, and the International GNSS Services (IGS) final tropospheric correction product, respectively. These data sets were generated at ten IGS reference stations spanning Canada and the United States. We analyzed the NOAATrop ZTD data series and compared them with those of the Hopfield model. The IGS final tropospheric product was used as a reference. The analysis shows that the performance of the NOAATrop model is a function of both season (time of the year) and geographical location. However, its performance was superior to the Hopfield model in all cases. We further investigated the effect of implementing the NOAATrop model on the ionosphere-free-based PPP solution convergence and accuracy. It is shown that the use of the NOAATrop model improved the PPP solution convergence by 1%, 10% and 15% for the latitude, longitude and height components, respectively

  12. Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency

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    Emily M. Mace

    2018-03-01

    Full Text Available Human natural killer (NK cells play a critical role in the control of viral infections and malignancy. Their importance in human health and disease is illustrated by severe viral infections in patients with primary immunodeficiencies that affect NK cell function and/or development. The recent identification of patients with phosphoinositide-3-kinase (PI3K-signaling pathway mutations that can cause primary immunodeficiency provides valuable insight into the role that PI3K signaling plays in human NK cell maturation and lytic function. There is a rich literature that demonstrates a requirement for PI3K in multiple key aspects of NK cell biology, including development/maturation, homing, priming, and function. Here, I briefly review these previous studies and place them in context with recent findings from the study of primary immunodeficiency patients, particularly those with hyperactivating mutations in PI3Kδ signaling.

  13. Influence of ER leak on resting cytoplasmic Ca2+ and receptor-mediated Ca2+ signalling in human macrophage.

    Science.gov (United States)

    Layhadi, Janice A; Fountain, Samuel J

    2017-06-03

    Mechanisms controlling endoplasmic reticulum (ER) Ca 2+ homeostasis are important regulators of resting cytoplasmic Ca 2+ concentration ([Ca 2+ ] cyto ) and receptor-mediated Ca 2+ signalling. Here we investigate channels responsible for ER Ca 2+ leak in THP-1 macrophage and human primary macrophage. In the absence of extracellular Ca 2+ we employ ionomycin action at the plasma membrane to stimulate ER Ca 2+ leak. Under these conditions ionomycin elevates [Ca 2+ ] cyto revealing a Ca 2+ leak response which is abolished by thapsigargin. IP 3 receptors (Xestospongin C, 2-APB), ryanodine receptors (dantrolene), and translocon (anisomycin) inhibition facilitated ER Ca 2+ leak in model macrophage, with translocon inhibition also reducing resting [Ca 2+ ] cyto . In primary macrophage, translocon inhibition blocks Ca 2+ leak but does not influence resting [Ca 2+ ] cyto . We identify a role for translocon-mediated ER Ca 2+ leak in receptor-mediated Ca 2+ signalling in both model and primary human macrophage, whereby the Ca 2+ response to ADP (P2Y receptor agonist) is augmented following anisomycin treatment. In conclusion, we demonstrate a role of ER Ca 2+ leak via the translocon in controlling resting cytoplasmic Ca 2+ in model macrophage and receptor-mediated Ca 2+ signalling in model macrophage and primary macrophage. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells

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    Chung Hyung-Min

    2009-08-01

    Full Text Available Abstract Background Studies have provided important findings about the roles of Notch signaling in neural development. Unfortunately, however, most of these studies have investigated the neural stem cells (NSCs of mice or other laboratory animals rather than humans, mainly owing to the difficulties associated with obtaining human brain samples. It prompted us to focus on neuroectodermal spheres (NESs which are derived from human embryonic stem cell (hESC and densely inhabited by NSCs. We here investigated the role of Notch signaling with the hESC-derived NESs. Results From hESCs, we derived NESs, the in-vitro version of brain-derived neurospheres. NES formation was confirmed by increased levels of various NSC marker genes and the emergence of rosette structures in which neuroprogenitors are known to reside. We found that Notch signaling, which maintains stem cell characteristics of in-vivo-derived neuroprogenitors, is active in these hESC-derived NESs, similar to their in-vivo counterpart. Expression levels of Notch signaling molecules such as NICD, DLLs, JAG1, HES1 and HES5 were increased in the NESs. Inhibition of the Notch signaling by a γ-secretase inhibitor reduced rosette structures, expression levels of NSC marker genes and proliferation potential in the NESs, and, if combined with withdrawal of growth factors, triggered differentiation toward neurons. Conclusion Our results indicate that the hESC-derived NESs, which share biochemical features with brain-derived neurospheres, maintain stem cell characteristics mainly through Notch signaling, which suggests that the hESC-derived NESs could be an in-vitro model for in-vivo neurogenesis.

  15. Statistical mechanics of learning orthogonal signals for general covariance models

    International Nuclear Information System (INIS)

    Hoyle, David C

    2010-01-01

    Statistical mechanics techniques have proved to be useful tools in quantifying the accuracy with which signal vectors are extracted from experimental data. However, analysis has previously been limited to specific model forms for the population covariance C, which may be inappropriate for real world data sets. In this paper we obtain new statistical mechanical results for a general population covariance matrix C. For data sets consisting of p sample points in R N we use the replica method to study the accuracy of orthogonal signal vectors estimated from the sample data. In the asymptotic limit of N,p→∞ at fixed α = p/N, we derive analytical results for the signal direction learning curves. In the asymptotic limit the learning curves follow a single universal form, each displaying a retarded learning transition. An explicit formula for the location of the retarded learning transition is obtained and we find marked variation in the location of the retarded learning transition dependent on the distribution of population covariance eigenvalues. The results of the replica analysis are confirmed against simulation

  16. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    International Nuclear Information System (INIS)

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-01-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As 2 O 3

  17. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Stueckle, Todd A., E-mail: tstueckle@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Lu, Yongju, E-mail: yongju6@hotmail.com [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Davis, Mary E., E-mail: mdavis@wvu.edu [Department of Physiology, West Virginia University, Morgantown, WV 26506 (United States); Wang, Liying, E-mail: lmw6@cdc.gov [Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Jiang, Bing-Hua, E-mail: bhjiang@jefferson.edu [Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Holaskova, Ida, E-mail: iholaskova@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Schafer, Rosana, E-mail: rschafer@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Barnett, John B., E-mail: jbarnett@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Rojanasakul, Yon, E-mail: yrojan@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States)

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As{sub 2}O

  18. Energy-Efficient Crowdsensing of Human Mobility and Signal Levels in Cellular Networks

    Science.gov (United States)

    Foremski, Paweł; Gorawski, Michał; Grochla, Krzysztof; Polys, Konrad

    2015-01-01

    The paper presents a practical application of the crowdsensing idea to measure human mobility and signal coverage in cellular networks. Currently, virtually everyone is carrying a mobile phone, which may be used as a sensor to gather research data by measuring, e.g., human mobility and radio signal levels. However, many users are unwilling to participate in crowdsensing experiments. This work begins with the analysis of the barriers for engaging people in crowdsensing. A survey showed that people who agree to participate in crowdsensing expect a minimum impact on their battery lifetime and phone usage habits. To address these requirements, this paper proposes an application for measuring the location and signal strength data based on energy-efficient GPS tracking, which allows one to perform the measurements of human mobility and radio signal levels with minimum energy utilization and without any engagement of the user. The method described combines measurements from the accelerometer with effective management of the GPS to monitor the user mobility with the decrease in battery lifetime by approximately 20%. To show the applicability of the proposed platform, the sample results of signal level distribution and coverage maps gathered for an LTE network and representing human mobility are shown. PMID:26340633

  19. Using the PLUM procedure of SPSS to fit unequal variance and generalized signal detection models.

    Science.gov (United States)

    DeCarlo, Lawrence T

    2003-02-01

    The recent addition of aprocedure in SPSS for the analysis of ordinal regression models offers a simple means for researchers to fit the unequal variance normal signal detection model and other extended signal detection models. The present article shows how to implement the analysis and how to interpret the SPSS output. Examples of fitting the unequal variance normal model and other generalized signal detection models are given. The approach offers a convenient means for applying signal detection theory to a variety of research.

  20. Modeling of Embedded Human Systems

    Science.gov (United States)

    2013-07-01

    ISAT study [7] for DARPA in 20051 concretized the notion of an embedded human, who is a necessary component of the system. The proposed work integrates...Technology, IEEE Transactions on, vol. 16, no. 2, pp. 229–244, March 2008. [7] C. J. Tomlin and S. S. Sastry, “Embedded humans,” tech. rep., DARPA ISAT

  1. Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang, E-mail: md_wzx7189@163.com

    2016-03-18

    Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression of Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.

  2. On scaling of human body models

    Directory of Open Access Journals (Sweden)

    Hynčík L.

    2007-10-01

    Full Text Available Human body is not an unique being, everyone is another from the point of view of anthropometry and mechanical characteristics which means that division of the human body population to categories like 5%-tile, 50%-tile and 95%-tile from the application point of view is not enough. On the other hand, the development of a particular human body model for all of us is not possible. That is why scaling and morphing algorithms has started to be developed. The current work describes the development of a tool for scaling of the human models. The idea is to have one (or couple of standard model(s as a base and to create other models based on these basic models. One has to choose adequate anthropometrical and biomechanical parameters that describe given group of humans to be scaled and morphed among.

  3. A Circuit Model of Real Time Human Body Hydration.

    Science.gov (United States)

    Asogwa, Clement Ogugua; Teshome, Assefa K; Collins, Stephen F; Lai, Daniel T H

    2016-06-01

    Changes in human body hydration leading to excess fluid losses or overload affects the body fluid's ability to provide the necessary support for healthy living. We propose a time-dependent circuit model of real-time human body hydration, which models the human body tissue as a signal transmission medium. The circuit model predicts the attenuation of a propagating electrical signal. Hydration rates are modeled by a time constant τ, which characterizes the individual specific metabolic function of the body part measured. We define a surrogate human body anthropometric parameter θ by the muscle-fat ratio and comparing it with the body mass index (BMI), we find theoretically, the rate of hydration varying from 1.73 dB/min, for high θ and low τ to 0.05 dB/min for low θ and high τ. We compare these theoretical values with empirical measurements and show that real-time changes in human body hydration can be observed by measuring signal attenuation. We took empirical measurements using a vector network analyzer and obtained different hydration rates for various BMI, ranging from 0.6 dB/min for 22.7 [Formula: see text] down to 0.04 dB/min for 41.2 [Formula: see text]. We conclude that the galvanic coupling circuit model can predict changes in the volume of the body fluid, which are essential in diagnosing and monitoring treatment of body fluid disorder. Individuals with high BMI would have higher time-dependent biological characteristic, lower metabolic rate, and lower rate of hydration.

  4. Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling

    Science.gov (United States)

    Lebensohn, Andres M; Dubey, Ramin; Neitzel, Leif R; Tacchelly-Benites, Ofelia; Yang, Eungi; Marceau, Caleb D; Davis, Eric M; Patel, Bhaven B; Bahrami-Nejad, Zahra; Travaglini, Kyle J; Ahmed, Yashi; Lee, Ethan; Carette, Jan E; Rohatgi, Rajat

    2016-01-01

    The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. DOI: http://dx.doi.org/10.7554/eLife.21459.001 PMID:27996937

  5. ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.

    Directory of Open Access Journals (Sweden)

    Rotem Kadir

    2016-03-01

    Full Text Available Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.

  6. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary.

    Science.gov (United States)

    Fowler, Paul A; Anderson, Richard A; Saunders, Philippa T; Kinnell, Hazel; Mason, J Ian; Evans, Dean B; Bhattacharya, Siladitya; Flannigan, Samantha; Franks, Stephen; Monteiro, Ana; O'Shaughnessy, Peter J

    2011-06-01

    Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking. The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary. We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members. The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow. Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies. We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1. Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells. The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation.

  7. Hierarchic stochastic modelling applied to intracellular Ca(2+ signals.

    Directory of Open Access Journals (Sweden)

    Gregor Moenke

    Full Text Available Important biological processes like cell signalling and gene expression have noisy components and are very complex at the same time. Mathematical analysis of such systems has often been limited to the study of isolated subsystems, or approximations are used that are difficult to justify. Here we extend a recently published method (Thurley and Falcke, PNAS 2011 which is formulated in observable system configurations instead of molecular transitions. This reduces the number of system states by several orders of magnitude and avoids fitting of kinetic parameters. The method is applied to Ca(2+ signalling. Ca(2+ is a ubiquitous second messenger transmitting information by stochastic sequences of concentration spikes, which arise by coupling of subcellular Ca(2+ release events (puffs. We derive analytical expressions for a mechanistic Ca(2+ model, based on recent data from live cell imaging, and calculate Ca(2+ spike statistics in dependence on cellular parameters like stimulus strength or number of Ca(2+ channels. The new approach substantiates a generic Ca(2+ model, which is a very convenient way to simulate Ca(2+ spike sequences with correct spiking statistics.

  8. Linear collider signal of anomaly mediated supersymmetry breaking model

    International Nuclear Information System (INIS)

    Ghosh Dilip Kumar; Kundu, Anirban; Roy, Probir; Roy, Sourov

    2001-01-01

    Though the minimal model of anomaly mediated supersymmetry breaking has been significantly constrained by recent experimental and theoretical work, there are still allowed regions of the parameter space for moderate to large values of tan β. We show that these regions will be comprehensively probed in a √s = 1 TeV e + e - linear collider. Diagnostic signals to this end are studied by zeroing in on a unique and distinct feature of a large class of models in this genre: a neutral winolike Lightest Supersymmetric Particle closely degenerate in mass with a winolike chargino. The pair production processes e + e - → e tilde L ± e tilde L ± , e tilde R ± e tilde R ± , e tilde L ± e tilde R ± , ν tilde anti ν tilde, χ tilde 1 0 χ tilde 2 0 , χ tilde 2 0 χ tilde 2 0 are all considered at √s = 1 TeV corresponding to the proposed TESLA linear collider in two natural categories of mass ordering in the sparticle spectra. The signals analysed comprise multiple combinations of fast charged leptons (any of which can act as the trigger) plus displaced vertices X D (any of which can be identified by a heavy ionizing track terminating in the detector) and/or associated soft pions with characteristic momentum distributions. (author)

  9. Monte Carlo modeling of human tooth optical coherence tomography imaging

    International Nuclear Information System (INIS)

    Shi, Boya; Meng, Zhuo; Wang, Longzhi; Liu, Tiegen

    2013-01-01

    We present a Monte Carlo model for optical coherence tomography (OCT) imaging of human tooth. The model is implemented by combining the simulation of a Gaussian beam with simulation for photon propagation in a two-layer human tooth model with non-parallel surfaces through a Monte Carlo method. The geometry and the optical parameters of the human tooth model are chosen on the basis of the experimental OCT images. The results show that the simulated OCT images are qualitatively consistent with the experimental ones. Using the model, we demonstrate the following: firstly, two types of photons contribute to the information of morphological features and noise in the OCT image of a human tooth, respectively. Secondly, the critical imaging depth of the tooth model is obtained, and it is found to decrease significantly with increasing mineral loss, simulated as different enamel scattering coefficients. Finally, the best focus position is located below and close to the dental surface by analysis of the effect of focus positions on the OCT signal and critical imaging depth. We anticipate that this modeling will become a powerful and accurate tool for a preliminary numerical study of the OCT technique on diseases of dental hard tissue in human teeth. (paper)

  10. Cascaded analysis of signal and noise propagation through a heterogeneous breast model

    International Nuclear Information System (INIS)

    Mainprize, James G.; Yaffe, Martin J.

    2010-01-01

    Purpose: The detectability of lesions in radiographic images can be impaired by patterns caused by the surrounding anatomic structures. The presence of such patterns is often referred to as anatomic noise. Others have previously extended signal and noise propagation theory to include variable background structure as an additional noise term and used in simulations for analysis by human and ideal observers. Here, the analytic forms of the signal and noise transfer are derived to obtain an exact expression for any input random distribution and the ''power law'' filter used to generate the texture of the tissue distribution. Methods: A cascaded analysis of propagation through a heterogeneous model is derived for x-ray projection through simulated heterogeneous backgrounds. This is achieved by considering transmission through the breast as a correlated amplification point process. The analytic forms of the cascaded analysis were compared to monoenergetic Monte Carlo simulations of x-ray propagation through power law structured backgrounds. Results: As expected, it was found that although the quantum noise power component scales linearly with the x-ray signal, the anatomic noise will scale with the square of the x-ray signal. There was a good agreement between results obtained using analytic expressions for the noise power and those from Monte Carlo simulations for different background textures, random input functions, and x-ray fluence. Conclusions: Analytic equations for the signal and noise properties of heterogeneous backgrounds were derived. These may be used in direct analysis or as a tool to validate simulations in evaluating detectability.

  11. Mathematical model with autoregressive process for electrocardiogram signals

    Science.gov (United States)

    Evaristo, Ronaldo M.; Batista, Antonio M.; Viana, Ricardo L.; Iarosz, Kelly C.; Szezech, José D., Jr.; Godoy, Moacir F. de

    2018-04-01

    The cardiovascular system is composed of the heart, blood and blood vessels. Regarding the heart, cardiac conditions are determined by the electrocardiogram, that is a noninvasive medical procedure. In this work, we propose autoregressive process in a mathematical model based on coupled differential equations in order to obtain the tachograms and the electrocardiogram signals of young adults with normal heartbeats. Our results are compared with experimental tachogram by means of Poincaré plot and dentrended fluctuation analysis. We verify that the results from the model with autoregressive process show good agreement with experimental measures from tachogram generated by electrical activity of the heartbeat. With the tachogram we build the electrocardiogram by means of coupled differential equations.

  12. Large-Signal DG-MOSFET Modelling for RFID Rectification

    Directory of Open Access Journals (Sweden)

    R. Rodríguez

    2016-01-01

    Full Text Available This paper analyses the undoped DG-MOSFETs capability for the operation of rectifiers for RFIDs and Wireless Power Transmission (WPT at microwave frequencies. For this purpose, a large-signal compact model has been developed and implemented in Verilog-A. The model has been numerically validated with a device simulator (Sentaurus. It is found that the number of stages to achieve the optimal rectifier performance is inferior to that required with conventional MOSFETs. In addition, the DC output voltage could be incremented with the use of appropriate mid-gap metals for the gate, as TiN. Minor impact of short channel effects (SCEs on rectification is also pointed out.

  13. Human sensorimotor communication: a theory of signaling in online social interactions.

    Science.gov (United States)

    Pezzulo, Giovanni; Donnarumma, Francesco; Dindo, Haris

    2013-01-01

    Although the importance of communication is recognized in several disciplines, it is rarely studied in the context of online social interactions and joint actions. During online joint actions, language and gesture are often insufficient and humans typically use non-verbal, sensorimotor forms of communication to send coordination signals. For example, when playing volleyball, an athlete can exaggerate her movements to signal her intentions to her teammates (say, a pass to the right) or to feint an adversary. Similarly, a person who is transporting a table together with a co-actor can push the table in a certain direction to signal where and when he intends to place it. Other examples of "signaling" are over-articulating in noisy environments and over-emphasizing vowels in child-directed speech. In all these examples, humans intentionally modify their action kinematics to make their goals easier to disambiguate. At the moment no formal theory exists of these forms of sensorimotor communication and signaling. We present one such theory that describes signaling as a combination of a pragmatic and a communicative action, and explains how it simplifies coordination in online social interactions. We cast signaling within a "joint action optimization" framework in which co-actors optimize the success of their interaction and joint goals rather than only their part of the joint action. The decision of whether and how much to signal requires solving a trade-off between the costs of modifying one's behavior and the benefits in terms of interaction success. Signaling is thus an intentional strategy that supports social interactions; it acts in concert with automatic mechanisms of resonance, prediction, and imitation, especially when the context makes actions and intentions ambiguous and difficult to read. Our theory suggests that communication dynamics should be studied within theories of coordination and interaction rather than only in terms of the maximization of information

  14. Human sensorimotor communication: a theory of signaling in online social interactions.

    Directory of Open Access Journals (Sweden)

    Giovanni Pezzulo

    Full Text Available Although the importance of communication is recognized in several disciplines, it is rarely studied in the context of online social interactions and joint actions. During online joint actions, language and gesture are often insufficient and humans typically use non-verbal, sensorimotor forms of communication to send coordination signals. For example, when playing volleyball, an athlete can exaggerate her movements to signal her intentions to her teammates (say, a pass to the right or to feint an adversary. Similarly, a person who is transporting a table together with a co-actor can push the table in a certain direction to signal where and when he intends to place it. Other examples of "signaling" are over-articulating in noisy environments and over-emphasizing vowels in child-directed speech. In all these examples, humans intentionally modify their action kinematics to make their goals easier to disambiguate. At the moment no formal theory exists of these forms of sensorimotor communication and signaling. We present one such theory that describes signaling as a combination of a pragmatic and a communicative action, and explains how it simplifies coordination in online social interactions. We cast signaling within a "joint action optimization" framework in which co-actors optimize the success of their interaction and joint goals rather than only their part of the joint action. The decision of whether and how much to signal requires solving a trade-off between the costs of modifying one's behavior and the benefits in terms of interaction success. Signaling is thus an intentional strategy that supports social interactions; it acts in concert with automatic mechanisms of resonance, prediction, and imitation, especially when the context makes actions and intentions ambiguous and difficult to read. Our theory suggests that communication dynamics should be studied within theories of coordination and interaction rather than only in terms of the

  15. Modeling multimodal human-computer interaction

    NARCIS (Netherlands)

    Obrenovic, Z.; Starcevic, D.

    2004-01-01

    Incorporating the well-known Unified Modeling Language into a generic modeling framework makes research on multimodal human-computer interaction accessible to a wide range off software engineers. Multimodal interaction is part of everyday human discourse: We speak, move, gesture, and shift our gaze

  16. 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

  17. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

    Science.gov (United States)

    Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J.; Campbell, Sean R.; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Chambers, Daniel B.; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M.; Liebelt, David A.; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J.; Louneva, Natalia; Arnold, Steven E.; Featherstone, Robert E.; Siegel, Steven J.; Zukin, R. Suzanne; McDonald, Thomas V.; Bolduc, Francois V.; Jongens, Thomas A.; McBride, Sean M. J.

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  18. Human female orgasm as evolved signal: a test of two hypotheses.

    Science.gov (United States)

    Ellsworth, Ryan M; Bailey, Drew H

    2013-11-01

    We present the results of a study designed to empirically test predictions derived from two hypotheses regarding human female orgasm behavior as an evolved communicative trait or signal. One hypothesis tested was the female fidelity hypothesis, which posits that human female orgasm signals a woman's sexual satisfaction and therefore her likelihood of future fidelity to a partner. The other was sire choice hypothesis, which posits that women's orgasm behavior signals increased chances of fertilization. To test the two hypotheses of human female orgasm, we administered a questionnaire to 138 females and 121 males who reported that they were currently in a romantic relationship. Key predictions of the female fidelity hypothesis were not supported. In particular, orgasm was not associated with female sexual fidelity nor was orgasm associated with male perceptions of partner sexual fidelity. However, faked orgasm was associated with female sexual infidelity and lower male relationship satisfaction. Overall, results were in greater support of the sire choice signaling hypothesis than the female fidelity hypothesis. Results also suggest that male satisfaction with, investment in, and sexual fidelity to a mate are benefits that favored the selection of orgasmic signaling in ancestral females.

  19. Quantitative Models of Imperfect Deception in Network Security using Signaling Games with Evidence

    OpenAIRE

    Pawlick, Jeffrey; Zhu, Quanyan

    2017-01-01

    Deception plays a critical role in many interactions in communication and network security. Game-theoretic models called "cheap talk signaling games" capture the dynamic and information asymmetric nature of deceptive interactions. But signaling games inherently model undetectable deception. In this paper, we investigate a model of signaling games in which the receiver can detect deception with some probability. This model nests traditional signaling games and complete information Stackelberg ...

  20. Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens.

    Science.gov (United States)

    Adel, Susan; Kakularam, Kumar Reddy; Horn, Thomas; Reddanna, Pallu; Kuhn, Hartmut; Heydeck, Dagmar

    2015-01-01

    Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins appeared to be corrupted. Meanwhile high quality genomic sequence data became available for two extinct human subspecies (H. neanderthalensis, Homo denisovan) and completion of the human 1000 genome project provided a comprehensive database characterizing the genetic variability of the human genome. For this study we extracted the nucleotide sequences of selected eicosanoid relevant genes (ALOX5, ALOX15, ALOX12, ALOX15B, ALOX12B, ALOXE3, COX1, COX2, LTA4H, LTC4S, ALOX5AP, CYSLTR1, CYSLTR2, BLTR1, BLTR2) from the corresponding databases. Comparison of the deduced amino acid sequences in connection with site-directed mutagenesis studies and structural modeling suggested that the major enzymes and receptors of leukotriene signaling as well as the two cyclooxygenase isoforms were fully functional in these two extinct human subspecies. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Hidden Markov Models for Human Genes

    DEFF Research Database (Denmark)

    Baldi, Pierre; Brunak, Søren; Chauvin, Yves

    1997-01-01

    We analyse the sequential structure of human genomic DNA by hidden Markov models. We apply models of widely different design: conventional left-right constructs and models with a built-in periodic architecture. The models are trained on segments of DNA sequences extracted such that they cover com...

  2. Expression of insulin signalling components in the sensory epithelium of the human saccule

    DEFF Research Database (Denmark)

    Degerman, Eva; Rauch, Uwe; Lindberg, Sven

    2013-01-01

    signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also...

  3. Onco-GPCR signaling and dysregulated expression of microRNAs in human cancer.

    Science.gov (United States)

    Nohata, Nijiro; Goto, Yusuke; Gutkind, J Silvio

    2017-01-01

    The G-protein-coupled receptor (GPCR) family is the largest family of cell-surface receptors involved in signal transduction. Aberrant expression of GPCRs and G proteins are frequently associated with prevalent human diseases, including cancer. In fact, GPCRs represent the therapeutic targets of more than a quarter of the clinical drugs currently on the market. MiRNAs (miRNAs) are also aberrantly expressed in many human cancers, and they have significant roles in the initiation, development and metastasis of human malignancies. Recent studies have revealed that dysregulation of miRNAs and their target genes expression are associated with cancer progression. The emerging information suggests that miRNAs play an important role in the fine tuning of many signaling pathways, including GPCR signaling. We summarize our current knowledge of the individual functions of miRNAs regulated by GPCRs and GPCR signaling-associated molecules, and miRNAs that regulate the expression and activity of GPCRs, their endogenous ligands and their coupled heterotrimeric G proteins in human cancer.

  4. On quantum models of the human mind.

    Science.gov (United States)

    Wang, Hongbin; Sun, Yanlong

    2014-01-01

    Recent years have witnessed rapidly increasing interests in developing quantum theoretical models of human cognition. Quantum mechanisms have been taken seriously to describe how the mind reasons and decides. Papers in this special issue report the newest results in the field. Here we discuss why the two levels of commitment, treating the human brain as a quantum computer and merely adopting abstract quantum probability principles to model human cognition, should be integrated. We speculate that quantum cognition models gain greater modeling power due to a richer representation scheme. Copyright © 2013 Cognitive Science Society, Inc.

  5. Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models.

    Science.gov (United States)

    Tan, Fenlai; Yang, Guiqun; Wang, Yanping; Chen, Haibo; Yu, Bo; Li, He; Guo, Jing; Huang, Xiaoling; Deng, Yifang; Yu, Pengxia; Ding, Lieming

    2018-02-01

    To investigate the effects of icotinib hydrochloride and a derivative cream on epidermal growth factor receptor (EGFR) signaling and within animal psoriasis models, respectively. The effect of icotinib on EGFR signaling was examined in HaCaT cells, while its effect on angiogenesis was tested in chick embryo chorioallantoic membranes (CAM). The effectiveness of icotinib in treating psoriasis was tested in three psoriasis models, including diethylstilbestrol-treated mouse vaginal epithelial cells, mouse tail granular cell layer formation, and propranolol-induced psoriasis-like features in guinea pig ear skin. Icotinib treatment blocked EGFR signaling and reduced HaCaT cell viability as well as suppressed CAM angiogenesis. Topical application of icotinib ameliorated psoriasis-like histological characteristics in mouse and guinea pig psoriasis models. Icotinib also significantly inhibited mouse vaginal epithelium mitosis, promoted mouse tail squamous epidermal granular layer formation, and reduced the thickness of the horny layer in propranolol treated auricular dorsal surface of guinea pig. We conclude that icotinib can effectively inhibit psoriasis in animal models. Future clinical studies should be conducted to explore the therapeutic effects of icotinb in humans. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Vitamin D controls T cell antigen receptor signaling and activation of human T cells

    DEFF Research Database (Denmark)

    von Essen, Marina Rode; Kongsbak-Wismann, Martin; Schjerling, Peter

    2010-01-01

    Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering...... led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR...... signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation....

  7. Src-family kinases negatively regulate NFAT signaling in resting human T cells.

    Directory of Open Access Journals (Sweden)

    Alan Baer

    Full Text Available T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood. Here, we characterized the role of active SFKs in resting human T cells. Pharmacologic inhibition of active SFKs enhanced distal TCR signaling as measured by IL-2 release and CD25 surface expression following TCR-independent activation. Mechanistically, inhibition of the active pool of SFKs induced nuclear translocation of NFAT1, and enhanced NFAT1-dependent signaling in resting T cells. The negative regulation of NFAT1 signaling was in part mediated by the Src-kinase Lck as human T cells lacking Lck had increased levels of nuclear NFAT1 and demonstrated enhanced NFAT1-dependent gene expression. Inhibition of active SFKs in resting primary human T cells also increased nuclear NFAT1 and enhanced NFAT1-dependent signaling. Finally, the calcineurin inhibitor FK506 and Cyclosporin A reversed the effect of SFKs inhibition on NFAT1. Together, these data identified a novel role of SFKs in preventing aberrant NFAT1 activation in resting T cells, and suggest that maintaining this pool of active SFKs in therapeutic T cells may increase the efficacy of T cell therapies.

  8. Cascading walks model for human mobility patterns.

    Science.gov (United States)

    Han, Xiao-Pu; Wang, Xiang-Wen; Yan, Xiao-Yong; Wang, Bing-Hong

    2015-01-01

    Uncovering the mechanism behind the scaling laws and series of anomalies in human trajectories is of fundamental significance in understanding many spatio-temporal phenomena. Recently, several models, e.g. the explorations-returns model (Song et al., 2010) and the radiation model for intercity travels (Simini et al., 2012), have been proposed to study the origin of these anomalies and the prediction of human movements. However, an agent-based model that could reproduce most of empirical observations without priori is still lacking. In this paper, considering the empirical findings on the correlations of move-lengths and staying time in human trips, we propose a simple model which is mainly based on the cascading processes to capture the human mobility patterns. In this model, each long-range movement activates series of shorter movements that are organized by the law of localized explorations and preferential returns in prescribed region. Based on the numerical simulations and analytical studies, we show more than five statistical characters that are well consistent with the empirical observations, including several types of scaling anomalies and the ultraslow diffusion properties, implying the cascading processes associated with the localized exploration and preferential returns are indeed a key in the understanding of human mobility activities. Moreover, the model shows both of the diverse individual mobility and aggregated scaling displacements, bridging the micro and macro patterns in human mobility. In summary, our model successfully explains most of empirical findings and provides deeper understandings on the emergence of human mobility patterns.

  9. Modelling noninvasively measured cerebral signals during a hypoxemia challenge: steps towards individualised modelling.

    Directory of Open Access Journals (Sweden)

    Beth Jelfs

    Full Text Available Noninvasive approaches to measuring cerebral circulation and metabolism are crucial to furthering our understanding of brain function. These approaches also have considerable potential for clinical use "at the bedside". However, a highly nontrivial task and precondition if such methods are to be used routinely is the robust physiological interpretation of the data. In this paper, we explore the ability of a previously developed model of brain circulation and metabolism to explain and predict quantitatively the responses of physiological signals. The five signals all noninvasively-measured during hypoxemia in healthy volunteers include four signals measured using near-infrared spectroscopy along with middle cerebral artery blood flow measured using transcranial Doppler flowmetry. We show that optimising the model using partial data from an individual can increase its predictive power thus aiding the interpretation of NIRS signals in individuals. At the same time such optimisation can also help refine model parametrisation and provide confidence intervals on model parameters. Discrepancies between model and data which persist despite model optimisation are used to flag up important questions concerning the underlying physiology, and the reliability and physiological meaning of the signals.

  10. Channel modeling, signal processing and coding for perpendicular magnetic recording

    Science.gov (United States)

    Wu, Zheng

    With the increasing areal density in magnetic recording systems, perpendicular recording has replaced longitudinal recording to overcome the superparamagnetic limit. Studies on perpendicular recording channels including aspects of channel modeling, signal processing and coding techniques are presented in this dissertation. To optimize a high density perpendicular magnetic recording system, one needs to know the tradeoffs between various components of the system including the read/write transducers, the magnetic medium, and the read channel. We extend the work by Chaichanavong on the parameter optimization for systems via design curves. Different signal processing and coding techniques are studied. Information-theoretic tools are utilized to determine the acceptable region for the channel parameters when optimal detection and linear coding techniques are used. Our results show that a considerable gain can be achieved by the optimal detection and coding techniques. The read-write process in perpendicular magnetic recording channels includes a number of nonlinear effects. Nonlinear transition shift (NLTS) is one of them. The signal distortion induced by NLTS can be reduced by write precompensation during data recording. We numerically evaluate the effect of NLTS on the read-back signal and examine the effectiveness of several write precompensation schemes in combating NLTS in a channel characterized by both transition jitter noise and additive white Gaussian electronics noise. We also present an analytical method to estimate the bit-error-rate and use it to help determine the optimal write precompensation values in multi-level precompensation schemes. We propose a mean-adjusted pattern-dependent noise predictive (PDNP) detection algorithm for use on the channel with NLTS. We show that this detector can offer significant improvements in bit-error-rate (BER) compared to conventional Viterbi and PDNP detectors. Moreover, the system performance can be further improved by

  11. Human Centered Hardware Modeling and Collaboration

    Science.gov (United States)

    Stambolian Damon; Lawrence, Brad; Stelges, Katrine; Henderson, Gena

    2013-01-01

    In order to collaborate engineering designs among NASA Centers and customers, to in clude hardware and human activities from multiple remote locations, live human-centered modeling and collaboration across several sites has been successfully facilitated by Kennedy Space Center. The focus of this paper includes innovative a pproaches to engineering design analyses and training, along with research being conducted to apply new technologies for tracking, immersing, and evaluating humans as well as rocket, vehic le, component, or faci lity hardware utilizing high resolution cameras, motion tracking, ergonomic analysis, biomedical monitoring, wor k instruction integration, head-mounted displays, and other innovative human-system integration modeling, simulation, and collaboration applications.

  12. Human Adaptive Mechatronics and Human-System Modelling

    Directory of Open Access Journals (Sweden)

    Satoshi Suzuki

    2013-03-01

    Full Text Available Several topics in projects for mechatronics studies, which are 'Human Adaptive Mechatronics (HAM' and 'Human-System Modelling (HSM', are presented in this paper. The main research theme of the HAM project is a design strategy for a new intelligent mechatronics system, which enhances operators' skills during machine operation. Skill analyses and control system design have been addressed. In the HSM project, human modelling based on hierarchical classification of skills was studied, including the following five types of skills: social, planning, cognitive, motion and sensory-motor skills. This paper includes digests of these research topics and the outcomes concerning each type of skill. Relationships with other research activities, knowledge and information that will be helpful for readers who are trying to study assistive human-mechatronics systems are also mentioned.

  13. Mathematical modeling and signal processing in speech and hearing sciences

    CERN Document Server

    Xin, Jack

    2014-01-01

    The aim of the book is to give an accessible introduction of mathematical models and signal processing methods in speech and hearing sciences for senior undergraduate and beginning graduate students with basic knowledge of linear algebra, differential equations, numerical analysis, and probability. Speech and hearing sciences are fundamental to numerous technological advances of the digital world in the past decade, from music compression in MP3 to digital hearing aids, from network based voice enabled services to speech interaction with mobile phones. Mathematics and computation are intimately related to these leaps and bounds. On the other hand, speech and hearing are strongly interdisciplinary areas where dissimilar scientific and engineering publications and approaches often coexist and make it difficult for newcomers to enter.

  14. Modeling and processing of laser Doppler reactive hyperaemia signals

    Science.gov (United States)

    Humeau, Anne; Saumet, Jean-Louis; L'Huiller, Jean-Pierre

    2003-07-01

    Laser Doppler flowmetry is a non-invasive method used in the medical domain to monitor the microvascular blood cell perfusion through tissue. Most commercial laser Doppler flowmeters use an algorithm calculating the first moment of the power spectral density to give the perfusion value. Many clinical applications measure the perfusion after a vascular provocation such as a vascular occlusion. The response obtained is then called reactive hyperaemia. Target pathologies include diabetes, hypertension and peripheral arterial occlusive diseases. In order to have a deeper knowledge on reactive hyperaemia acquired by the laser Doppler technique, the present work first proposes two models (one analytical and one numerical) of the observed phenomenon. Then, a study on the multiple scattering between photons and red blood cells occurring during reactive hyperaemia is carried out. Finally, a signal processing that improves the diagnosis of peripheral arterial occlusive diseases is presented.

  15. Modelling human factor with Petri nets

    International Nuclear Information System (INIS)

    Bedreaga, Luminita; Constantinescu, Cristina; Guzun, Basarab

    2007-01-01

    The human contribution to risk and safety of nuclear power plant operation can be best understood, assessed and quantified using tools to evaluate human reliability. Human reliability analysis becomes an important part of every probabilistic safety assessment and it is used to demonstrate that nuclear power plants designed with different safety levels are prepared to cope with severe accidents. Human reliability analysis in context of probabilistic safety assessment consists in: identifying human-system interactions important to safety; quantifying probabilities appropriate with these interactions. Nowadays, the complex system functions can be modelled using special techniques centred either on states space adequate to system or on events appropriate to the system. Knowing that complex system model consists in evaluating the likelihood of success, in other words, in evaluating the possible value for that system being in some state, the inductive methods which are based on the system states can be applied also for human reliability modelling. Thus, switching to the system states taking into account the human interactions, the underlying basis of the Petri nets can be successfully applied and the likelihoods appropriate to these states can also derived. The paper presents the manner to assess the human reliability quantification using Petri nets approach. The example processed in the paper is from human reliability documentation without a detailed human factor analysis (qualitative). The obtained results by these two kinds of methods are in good agreement. (authors)

  16. Inequality signals in dorsolateral prefrontal cortex inform social preference models.

    Science.gov (United States)

    Holper, Lisa; Burke, Christopher J; Fausch, Christoph; Seifritz, Erich; Tobler, Philippe N

    2018-05-01

    Humans typically display inequality aversion in social situations, which manifests itself as a preference for fairer distributions of resources. However, people differ in the degree to which they dislike being worse off [disadvantageous inequality (DI) aversion] or better off [advantageous inequality (AI) aversion] than others. Competing models explain such behavior by focusing on aversion to payoff differences, maximization of total payoff or reciprocity. Using functional near-infrared spectroscopy, we asked which of these theories could better explain dorsolateral prefrontal cortex (dlPFC) activity while participants accepted or punished fair vs unfair monetary transfers in an anonymous norm compliance task. We found that while all participants exhibited DI aversion, there were substantial differences in preferences for AI, which were strongly predicted by dlPFC activation. Model comparisons revealed that both punishment behavior and prefrontal activity were best explained by a model that allowed for AI seeking rather than imposing aversion. Moreover, enhancing this model by taking into account behavioral response times, as a proxy for choice difficulty, further improved model fits. Our data provide evidence that the dlPFC encodes subjective values of payoff inequality and that this representation is richer than envisaged by standard models of social preferences.

  17. Desloratadine citrate disodium injection, a potent histamine H(1) receptor antagonist, inhibits chemokine production in ovalbumin-induced allergic rhinitis guinea pig model and histamine-induced human nasal epithelial cells via inhibiting the ERK1/2 and NF-kappa B signal cascades.

    Science.gov (United States)

    Chen, Meiling; Xu, Shuhong; Zhou, Peipei; He, Guangwei; Jie, Qiong; Wu, Yulin

    2015-11-15

    Chemokines have chemotactic properties on leukocyte subsets whose modulation plays a pivotal role in allergic inflammatory processes. Our present study was designed to investigate the anti-allergic and anti-inflammatory properties of desloratadine citrate disodium injection (DLC) and elucidate the molecular mechanisms of its anti-inflammatory properties. The anti-allergic effects of DLC were evaluated based on allergic symptoms, serological marker production and histological changes of the nasal mucosa in guinea pigs model of allergic rhinitis. The anti-inflammatory properties and molecular mechanisms of DLC were explored by studying the regulation of a set of chemokines and extracellular signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) pathways, after DLC treatment in guinea pigs model of allergic rhinitis in vivo and histamine-activated human nasal epithelial cells (HNECs) in vitro. In vivo model in guinea pigs, DLC alleviated the rhinitis symptoms, inhibited inflammatory cells infiltration in nasal lavage fluid (NLF) and histamine, monocyte chemotactic protein (MCP)-1, regulated on activation normal T cell expressed, and presumably secreted (RANTEs) and interleukin (IL)-8 release in sera and P-ERK1/2 and NF-κB activation in nasal mucosa. In vitro, DLC markedly inhibited histamine-induced production of MCP-1, RANTEs and IL-8 and suppressed c-Raf, mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and ERK1/2 activation in HNECs. These results provide evidence that DLC possesses potent anti-allergic and anti-inflammatory properties. The mechanism of action underlying DLC in allergic inflammation appears to be inhibition of the phosphorylation of ERK1/2, in addition to blocking of the NF-κB pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Decoding Speech With Integrated Hybrid Signals Recorded From the Human Ventral Motor Cortex

    Directory of Open Access Journals (Sweden)

    Kenji Ibayashi

    2018-04-01

    Full Text Available Restoration of speech communication for locked-in patients by means of brain computer interfaces (BCIs is currently an important area of active research. Among the neural signals obtained from intracranial recordings, single/multi-unit activity (SUA/MUA, local field potential (LFP, and electrocorticography (ECoG are good candidates for an input signal for BCIs. However, the question of which signal or which combination of the three signal modalities is best suited for decoding speech production remains unverified. In order to record SUA, LFP, and ECoG simultaneously from a highly localized area of human ventral sensorimotor cortex (vSMC, we fabricated an electrode the size of which was 7 by 13 mm containing sparsely arranged microneedle and conventional macro contacts. We determined which signal modality is the most capable of decoding speech production, and tested if the combination of these signals could improve the decoding accuracy of spoken phonemes. Feature vectors were constructed from spike frequency obtained from SUAs and event-related spectral perturbation derived from ECoG and LFP signals, then input to the decoder. The results showed that the decoding accuracy for five spoken vowels was highest when features from multiple signals were combined and optimized for each subject, and reached 59% when averaged across all six subjects. This result suggests that multi-scale signals convey complementary information for speech articulation. The current study demonstrated that simultaneous recording of multi-scale neuronal activities could raise decoding accuracy even though the recording area is limited to a small portion of cortex, which is advantageous for future implementation of speech-assisting BCIs.

  19. Modeling the photoacoustic signal during the porous silicon formation

    Science.gov (United States)

    Ramirez-Gutierrez, C. F.; Castaño-Yepes, J. D.; Rodriguez-García, M. E.

    2017-01-01

    Within this work, the kinetics of the growing stage of porous silicon (PS) during the etching process was studied using the photoacoustic technique. A p-type Si with low resistivity was used as a substrate. An extension of the Rosencwaig and Gersho model is proposed in order to analyze the temporary changes that take place in the amplitude of the photoacoustic signal during the PS growth. The solution of the heat equation takes into account the modulated laser beam, the changes in the reflectance of the PS-backing heterostructure, the electrochemical reaction, and the Joule effect as thermal sources. The model includes the time-dependence of the sample thickness during the electrochemical etching of PS. The changes in the reflectance are identified as the laser reflections in the internal layers of the system. The reflectance is modeled by an additional sinusoidal-monochromatic light source and its modulated frequency is related to the velocity of the PS growth. The chemical reaction and the DC components of the heat sources are taken as an average value from the experimental data. The theoretical results are in agreement with the experimental data and hence provided a method to determine variables of the PS growth, such as the etching velocity and the thickness of the porous layer during the growing process.

  20. Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells

    International Nuclear Information System (INIS)

    Shen, Longxiang; Glowacki, Julie; Zhou, Shuanhu

    2011-01-01

    The WNT signaling pathway plays important roles in the self-renewal and differentiation of mesenchymal stem cells (MSCs). Little is known about WNT signaling in adipocyte differentiation of human MSCs. In this study, we tested the hypothesis that canonical and non-canonical WNTs differentially regulate in vitro adipocytogenesis in human MSCs. The expression of adipocyte gene PPARγ2, lipoprotein lipase, and adipsin increased during adipocytogenesis of hMSCs. Simultaneously, the expression of canonical WNT2, 10B, 13, and 14 decreased, whereas non-canonical WNT4 and 11 increased, and WNT5A was unchanged. A small molecule WNT mimetic, SB-216763, increased accumulation of β-catenin protein, inhibited induction of WNT4 and 11 and inhibited adipocytogenesis. In contrast, knockdown of β-catenin with siRNA resulted in spontaneous adipocytogenesis. These findings support the view that canonical WNT signaling inhibits and non-canonical WNT signaling promotes adipocytogenesis in adult human marrow-derived mesenchymal stem cells.

  1. Imaging of endogenous exchangeable proton signals in the human brain using frequency labeled exchange transfer imaging.

    Science.gov (United States)

    Yadav, Nirbhay N; Jones, Craig K; Hua, Jun; Xu, Jiadi; van Zijl, Peter C M

    2013-04-01

    To image endogenous exchangeable proton signals in the human brain using a recently reported method called frequency labeled exchange transfer (FLEX) MRI. As opposed to labeling exchangeable protons using saturation (i.e., chemical exchange saturation transfer, or CEST), FLEX labels exchangeable protons with their chemical shift evolution. The use of short high-power frequency pulses allows more efficient labeling of rapidly exchanging protons, while time domain acquisition allows removal of contamination from semi-solid magnetization transfer effects. FLEX-based exchangeable proton signals were detected in human brain over the 1-5 ppm frequency range from water. Conventional magnetization transfer contrast and the bulk water signal did not interfere in the FLEX spectrum. The information content of these signals differed from in vivo CEST data in that the average exchange rate of these signals was 350-400 s(-1) , much faster than the amide signal usually detected using direct saturation (∼30 s(-1) ). Similarly, fast exchanging protons could be detected in egg white in the same frequency range where amide and amine protons of mobile proteins and peptides are known to resonate. FLEX MRI in the human brain preferentially detects more rapidly exchanging amide/amine protons compared to traditional CEST experiments, thereby changing the information content of the exchangeable proton spectrum. This has the potential to open up different types of endogenous applications as well as more easy detection of rapidly exchanging protons in diaCEST agents or fast exchanging units such as water molecules in paracest agents without interference of conventional magnetization transfer contrast. Copyright © 2013 Wiley Periodicals, Inc.

  2. Neuroelectronics and modeling of electrical signals for monitoring and control of Parkinson's disease

    Science.gov (United States)

    Chintakuntla, Ritesh R.; Abraham, Jose K.; Varadan, Vijay K.

    2009-03-01

    The brain and the human nervous system are perhaps the most researched but least understood components of the human body. This is so because of the complex nature of its working and the high density of functions. The monitoring of neural signals could help one better understand the working of the brain and newer recording and monitoring methods have been developed ever since it was discovered that the brain communicates internally by means of electrical pulses. Neuroelectronics is the field which deals with the interface between electronics or semiconductors to living neurons. This includes monitoring of electrical activity from the brain as well as the development of feedback devices for stimulation of parts of the brain for treatment of disorders. In this paper these electrical signals are modeled through a nano/microelectrode arrays based on the electronic equivalent model using Cadence PSD 15.0. The results were compared with those previously published models such as Kupfmuller and Jenik's model, McGrogan's Neuron Model which are based on the Hodgkin and Huxley model. We have developed and equivalent circuit model using discrete passive components to simulate the electrical activity of the neurons. The simulated circuit can be easily be modified by adding some more ionic channels and the results can be used to predict necessary external stimulus needed for stimulation of neurons affected by the Parkinson's disease (PD). Implementing such a model in PD patients could predict the necessary voltages required for the electrical stimulation of the sub-thalamus region for the control tremor motion.

  3. Modeling human disease using organotypic cultures

    DEFF Research Database (Denmark)

    Schweiger, Pawel J; Jensen, Kim B

    2016-01-01

    animal models and in vitro cell culture systems. However, it has been exceedingly difficult to model disease at the tissue level. Since recently, the gap between cell line studies and in vivo modeling has been narrowing thanks to progress in biomaterials and stem cell research. Development of reliable 3D...... culture systems has enabled a rapid expansion of sophisticated in vitro models. Here we focus on some of the latest advances and future perspectives in 3D organoids for human disease modeling....

  4. Detection of chaotic dynamics in human gait signals from mobile devices

    Science.gov (United States)

    DelMarco, Stephen; Deng, Yunbin

    2017-05-01

    The ubiquity of mobile devices offers the opportunity to exploit device-generated signal data for biometric identification, health monitoring, and activity recognition. In particular, mobile devices contain an Inertial Measurement Unit (IMU) that produces acceleration and rotational rate information from the IMU accelerometers and gyros. These signals reflect motion properties of the human carrier. It is well-known that the complexity of bio-dynamical systems gives rise to chaotic dynamics. Knowledge of chaotic properties of these systems has shown utility, for example, in detecting abnormal medical conditions and neurological disorders. Chaotic dynamics has been found, in the lab, in bio-dynamical systems data such as electrocardiogram (heart), electroencephalogram (brain), and gait data. In this paper, we investigate the following question: can we detect chaotic dynamics in human gait as measured by IMU acceleration and gyro data from mobile phones? To detect chaotic dynamics, we perform recurrence analysis on real gyro and accelerometer signal data obtained from mobile devices. We apply the delay coordinate embedding approach from Takens' theorem to reconstruct the phase space trajectory of the multi-dimensional gait dynamical system. We use mutual information properties of the signal to estimate the appropriate delay value, and the false nearest neighbor approach to determine the phase space embedding dimension. We use a correlation dimension-based approach together with estimation of the largest Lyapunov exponent to make the chaotic dynamics detection decision. We investigate the ability to detect chaotic dynamics for the different one-dimensional IMU signals, across human subject and walking modes, and as a function of different phone locations on the human carrier.

  5. A human torque teno virus encodes a microRNA that inhibits interferon signaling.

    Directory of Open Access Journals (Sweden)

    Rodney P Kincaid

    Full Text Available Torque teno viruses (TTVs are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production in vivo. The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT interactor (NMI as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3'UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.

  6. Modeling Human Elements of Decision-Making

    Science.gov (United States)

    2002-06-01

    include factors such as personality, emotion , and level of expertise, which vary from individual to individual. The process of decision - making during... rational choice theories such as utility theory, to more descriptive psychological models that focus more on the process of decision - making ...descriptive nature, they provide a more realistic representation of human decision - making than the rationally based models. However these models do

  7. The Value of Human Capital Signals for Investment Decision Making under Uncertainty

    DEFF Research Database (Denmark)

    Hain, Daniel; Christensen, Jesper Lindgaard; Jurowetzki, Roman

    environments as our empirical setting. A large body of research from behavioral economics illustrates that when faced with uncertain and complex decision problems, investors tend to rely on simple heuristics and rules-of thumb, derived by easily accessible and assessable signals. Yet, with increasing...... with a similar pair that did lead to an investment. Based on Crunchbase investment data, we gather via LinkedIn and further sources detailed information on the founders professional and education background. We find human capital signals from the entrepreneurs to be of higher importance for investors when...

  8. Controlling a human-computer interface system with a novel classification method that uses electrooculography signals.

    Science.gov (United States)

    Wu, Shang-Lin; Liao, Lun-De; Lu, Shao-Wei; Jiang, Wei-Ling; Chen, Shi-An; Lin, Chin-Teng

    2013-08-01

    Electrooculography (EOG) signals can be used to control human-computer interface (HCI) systems, if properly classified. The ability to measure and process these signals may help HCI users to overcome many of the physical limitations and inconveniences in daily life. However, there are currently no effective multidirectional classification methods for monitoring eye movements. Here, we describe a classification method used in a wireless EOG-based HCI device for detecting eye movements in eight directions. This device includes wireless EOG signal acquisition components, wet electrodes and an EOG signal classification algorithm. The EOG classification algorithm is based on extracting features from the electrical signals corresponding to eight directions of eye movement (up, down, left, right, up-left, down-left, up-right, and down-right) and blinking. The recognition and processing of these eight different features were achieved in real-life conditions, demonstrating that this device can reliably measure the features of EOG signals. This system and its classification procedure provide an effective method for identifying eye movements. Additionally, it may be applied to study eye functions in real-life conditions in the near future.

  9. NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Hayashi, Yoshihiro; Osanai, Makoto; Lee, Gang-Hong

    2015-10-01

    The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1‑positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells.

  10. Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

    Directory of Open Access Journals (Sweden)

    Christopher K McCann

    Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C, no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

  11. Animal models for human genetic diseases

    African Journals Online (AJOL)

    Sharif Sons

    The study of human genetic diseases can be greatly aided by animal models because of their similarity .... and gene targeting in embryonic stem cells) has been a powerful tool in .... endonucleases that are designed to make a doublestrand.

  12. Human BDCM Mulit-Route PBPK Model

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set contains the code for the BDCM human multi-route model written in the programming language acsl. The final published manuscript is provided since it...

  13. A signaling model of foreign direct investment attraction

    Directory of Open Access Journals (Sweden)

    Marcelo de C. Griebeler

    2017-09-01

    Full Text Available Foreign direct investors face uncertainty about government's type of the host country. In a two period game, we allow the host country's government to mitigate such uncertainty by sending a signal through fiscal policy. Our main finding states that a populist government may mimic a conservative one in order to attract foreign direct investment (FDI, and this choice depends mainly on its impatience degree and the originally planned FDI stock. We highlight the role of the government's reputation in attracting foreign capital and thus provide some policy implications. Moreover, our model explains why some governments considered to be populist adopt conservative policies in the beginning of its terms of office. Resumo: Investidores estrangeiros diretos são incertos sobre o tipo do governo do país onde desejam investir. Em um jogo de dois períodos, permitimos que o governo de tal país mitigue essa incerteza ao enviar um sinal através da política fiscal. Nosso principal resultado estabelece que um governo populista pode imitar um conservador a fim de atrair investimento estrangeiro direto (IED, e essa escolha depende principalmente do grau de impaciência e do estoque de IED originalmente planejado. Destacamos o papel da reputação do governo em atrair capital externo e assim fornecemos algumas recomendações de política. Além disso, nosso modelo explica porque alguns governos considerados populistas adotam políticas conservadores no início do seus mandatos. JEL classification: F41, F34, C72, Keywords: Signaling, Foreign direct investment, Game theory, Palavras-chave: Sinalização, Investimento estrangeiro direto, Teoria dos jogos

  14. Human physiological models of insomnia.

    Science.gov (United States)

    Richardson, Gary S

    2007-12-01

    Despite the wide prevalence and important consequences of insomnia, remarkably little is known about its pathophysiology. Available models exist primarily in the psychological domain and derive from the demonstrated efficacy of behavioral treatment approaches to insomnia management. However, these models offer little specific prediction about the anatomic or physiological foundation of chronic primary insomnia. On the other hand, a growing body of data on the physiology of sleep supports a reasonably circumscribed overview of possible pathophysiological mechanisms, as well as the development of physiological models of insomnia to guide future research. As a pragmatic step, these models focus on primary insomnia, as opposed to comorbid insomnias, because the latter is by its nature a much more heterogeneous presentation, reflecting the effects of the distinct comorbid condition. Current understanding of the regulation of sleep and wakefulness in mammalian brain supports four broad candidate areas: 1) disruption of the sleep homeostat; 2) disruption of the circadian clock; 3) disruption of intrinsic systems responsible for the expression of sleep states; or 4) disruption (hyperactivity) of extrinsic systems capable of over-riding normal sleep-wake regulation. This review examines each of the four candidate pathophysiological mechanisms and the available data in support of each. While studies that directly test the viability of each model are not yet available, descriptive data on primary insomnia favor the involvement of dysfunctional extrinsic stress-response systems in the pathology of primary chronic insomnia.

  15. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

  16. Reinforcement learning signals in the human striatum distinguish learners from nonlearners during reward-based decision making.

    Science.gov (United States)

    Schönberg, Tom; Daw, Nathaniel D; Joel, Daphna; O'Doherty, John P

    2007-11-21

    The computational framework of reinforcement learning has been used to forward our understanding of the neural mechanisms underlying reward learning and decision-making behavior. It is known that humans vary widely in their performance in decision-making tasks. Here, we used a simple four-armed bandit task in which subjects are almost evenly split into two groups on the basis of their performance: those who do learn to favor choice of the optimal action and those who do not. Using models of reinforcement learning we sought to determine the neural basis of these intrinsic differences in performance by scanning both groups with functional magnetic resonance imaging. We scanned 29 subjects while they performed the reward-based decision-making task. Our results suggest that these two groups differ markedly in the degree to which reinforcement learning signals in the striatum are engaged during task performance. While the learners showed robust prediction error signals in both the ventral and dorsal striatum during learning, the nonlearner group showed a marked absence of such signals. Moreover, the magnitude of prediction error signals in a region of dorsal striatum correlated significantly with a measure of behavioral performance across all subjects. These findings support a crucial role of prediction error signals, likely originating from dopaminergic midbrain neurons, in enabling learning of action selection preferences on the basis of obtained rewards. Thus, spontaneously observed individual differences in decision making performance demonstrate the suggested dependence of this type of learning on the functional integrity of the dopaminergic striatal system in humans.

  17. Modeling Human Cancers in Drosophila.

    Science.gov (United States)

    Sonoshita, M; Cagan, R L

    2017-01-01

    Cancer is a complex disease that affects multiple organs. Whole-body animal models provide important insights into oncology that can lead to clinical impact. Here, we review novel concepts that Drosophila studies have established for cancer biology, drug discovery, and patient therapy. Genetic studies using Drosophila have explored the roles of oncogenes and tumor-suppressor genes that when dysregulated promote cancer formation, making Drosophila a useful model to study multiple aspects of transformation. Not limited to mechanism analyses, Drosophila has recently been showing its value in facilitating drug development. Flies offer rapid, efficient platforms by which novel classes of drugs can be identified as candidate anticancer leads. Further, we discuss the use of Drosophila as a platform to develop therapies for individual patients by modeling the tumor's genetic complexity. Drosophila provides both a classical and a novel tool to identify new therapeutics, complementing other more traditional cancer tools. © 2017 Elsevier Inc. All rights reserved.

  18. The Human-Artifact Model

    DEFF Research Database (Denmark)

    Bødker, Susanne; Klokmose, Clemens Nylandsted

    2011-01-01

    Although devices of all shapes and sizes currently dominate the technological landscape, human–computer interaction (HCI) as a field is not yet theoretically equipped to match this reality. In this article we develop the human–artifact model, which has its roots in activity theoretical HCI....... By reinterpreting the activity theoretical foundation, we present a framework that helps addressing the analysis of individual interactive artifacts while embracing that they are part of a larger ecology of artifacts. We show how the human–artifact model helps structuring the understanding of an artifact's action......-possibilities in relation to the artifact ecology surrounding it. Essential to the model is that it provides four interconnected levels of analysis and addresses the possibilities and problems at these four levels. Artifacts and their use are constantly developing, and we address development in, and of, use. The framework...

  19. Modeling Human Information Acquisition Strategies

    NARCIS (Netherlands)

    Heuvelink, Annerieke; Klein, Michel C. A.; van Lambalgen, Rianne; Taatgen, Niels A.; Rijn, Hedderik van

    2009-01-01

    The focus of this paper is the development of a computational model for intelligent agents that decides on whether to acquire required information by retrieving it from memory or by interacting with the world. First, we present a task for which such decisions have to be made. Next, we discuss an

  20. Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

    Science.gov (United States)

    Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

    2017-09-01

    Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  1. An Adaptive S-Method to Analyze Micro-Doppler Signals for Human Activity Classification.

    Science.gov (United States)

    Li, Fangmin; Yang, Chao; Xia, Yuqing; Ma, Xiaolin; Zhang, Tao; Zhou, Zhou

    2017-11-29

    In this paper, we propose the multiwindow Adaptive S-method (AS-method) distribution approach used in the time-frequency analysis for radar signals. Based on the results of orthogonal Hermite functions that have good time-frequency resolution, we vary the length of window to suppress the oscillating component caused by cross-terms. This method can bring a better compromise in the auto-terms concentration and cross-terms suppressing, which contributes to the multi-component signal separation. Finally, the effective micro signal is extracted by threshold segmentation and envelope extraction. To verify the proposed method, six states of motion are separated by a classifier of a support vector machine (SVM) trained to the extracted features. The trained SVM can detect a human subject with an accuracy of 95.4% for two cases without interference.

  2. An Adaptive S-Method to Analyze Micro-Doppler Signals for Human Activity Classification

    Directory of Open Access Journals (Sweden)

    Fangmin Li

    2017-11-01

    Full Text Available In this paper, we propose the multiwindow Adaptive S-method (AS-method distribution approach used in the time-frequency analysis for radar signals. Based on the results of orthogonal Hermite functions that have good time-frequency resolution, we vary the length of window to suppress the oscillating component caused by cross-terms. This method can bring a better compromise in the auto-terms concentration and cross-terms suppressing, which contributes to the multi-component signal separation. Finally, the effective micro signal is extracted by threshold segmentation and envelope extraction. To verify the proposed method, six states of motion are separated by a classifier of a support vector machine (SVM trained to the extracted features. The trained SVM can detect a human subject with an accuracy of 95.4% for two cases without interference.

  3. Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

    DEFF Research Database (Denmark)

    Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

    2018-01-01

    during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor......Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling...... signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand...

  4. Stretch activates human myometrium via ERK, caldesmon and focal adhesion signaling.

    Directory of Open Access Journals (Sweden)

    Yunping Li

    2009-10-01

    Full Text Available An incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility.

  5. Measures of metacognition on signal-detection theoretic models.

    Science.gov (United States)

    Barrett, Adam B; Dienes, Zoltan; Seth, Anil K

    2013-12-01

    Analyzing metacognition, specifically knowledge of accuracy of internal perceptual, memorial, or other knowledge states, is vital for many strands of psychology, including determining the accuracy of feelings of knowing and discriminating conscious from unconscious cognition. Quantifying metacognitive sensitivity is however more challenging than quantifying basic stimulus sensitivity. Under popular signal-detection theory (SDT) models for stimulus classification tasks, approaches based on Type II receiver-operating characteristic (ROC) curves or Type II d-prime risk confounding metacognition with response biases in either the Type I (classification) or Type II (metacognitive) tasks. A new approach introduces meta-d': The Type I d-prime that would have led to the observed Type II data had the subject used all the Type I information. Here, we (a) further establish the inconsistency of the Type II d-prime and ROC approaches with new explicit analyses of the standard SDT model and (b) analyze, for the first time, the behavior of meta-d' under nontrivial scenarios, such as when metacognitive judgments utilize enhanced or degraded versions of the Type I evidence. Analytically, meta-d' values typically reflect the underlying model well and are stable under changes in decision criteria; however, in relatively extreme cases, meta-d' can become unstable. We explore bias and variance of in-sample measurements of meta-d' and supply MATLAB code for estimation in general cases. Our results support meta-d' as a useful measure of metacognition and provide rigorous methodology for its application. Our recommendations are useful for any researchers interested in assessing metacognitive accuracy. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  6. Detection of Signal Regulatory Protein α in Saimiri sciureus (Squirrel Monkey) by Anti-Human Monoclonal Antibody

    Science.gov (United States)

    de Souza, Hugo Amorim dos Santos; Costa-Correa, Edmar Henrique; Bianco-Junior, Cesare; Andrade, Márcia Cristina Ribeiro; Lima-Junior, Josué da Costa; Pratt-Riccio, Lilian Rose; Daniel-Ribeiro, Cláudio Tadeu; Totino, Paulo Renato Rivas

    2017-01-01

    Non-human primates (NHP) are suitable models for studying different aspects of the human system, including pathogenesis and protective immunity to many diseases. However, the lack of specific immunological reagents for neo-tropical monkeys, such as Saimiri sciureus, is still a major factor limiting studies in these models. An alternative strategy to circumvent this obstacle has been the selection of immunological reagents directed to humans, which present cross-reactivity with NHP molecules. In this context and considering the key role of inhibitory immunoreceptors—such as the signal regulatory protein α (SIRPα)—in the regulation of immune responses, in the present study, we attempted to evaluate the ability of anti-human SIRPα monoclonal antibodies to recognize SIRPα in antigen-presenting S. sciureus peripheral blood mononuclear cells (PBMC). As shown by flow cytometry analysis, the profile of anti-SIRPα staining as well as the levels of SIRPα-positive cells in PBMC from S. sciureus were similar to those observed in human PBMC. Furthermore, using anti-SIRPα monoclonal antibody, it was possible to detect a decrease of the SIRPα levels on surface of S. sciureus cells after in vitro stimulation with lipopolysaccharides. Finally, using computed-based analysis, we observed a high degree of conservation of SIRPα across six species of primates and the presence of shared epitopes in the extracellular domain between humans and Saimiri genus that could be targeted by antibodies. In conclusion, we have identified a commercially available anti-human monoclonal antibody that is able to detect SIRPα of S. sciureus monkeys and that, therefore, can facilitate the study of the immunomodulatory role of SIRPα when S. sciureus is used as a model. PMID:29312325

  7. Detection of Signal Regulatory Protein α in Saimiri sciureus (Squirrel Monkey by Anti-Human Monoclonal Antibody

    Directory of Open Access Journals (Sweden)

    Hugo Amorim dos Santos de Souza

    2017-12-01

    Full Text Available Non-human primates (NHP are suitable models for studying different aspects of the human system, including pathogenesis and protective immunity to many diseases. However, the lack of specific immunological reagents for neo-tropical monkeys, such as Saimiri sciureus, is still a major factor limiting studies in these models. An alternative strategy to circumvent this obstacle has been the selection of immunological reagents directed to humans, which present cross-reactivity with NHP molecules. In this context and considering the key role of inhibitory immunoreceptors—such as the signal regulatory protein α (SIRPα—in the regulation of immune responses, in the present study, we attempted to evaluate the ability of anti-human SIRPα monoclonal antibodies to recognize SIRPα in antigen-presenting S. sciureus peripheral blood mononuclear cells (PBMC. As shown by flow cytometry analysis, the profile of anti-SIRPα staining as well as the levels of SIRPα-positive cells in PBMC from S. sciureus were similar to those observed in human PBMC. Furthermore, using anti-SIRPα monoclonal antibody, it was possible to detect a decrease of the SIRPα levels on surface of S. sciureus cells after in vitro stimulation with lipopolysaccharides. Finally, using computed-based analysis, we observed a high degree of conservation of SIRPα across six species of primates and the presence of shared epitopes in the extracellular domain between humans and Saimiri genus that could be targeted by antibodies. In conclusion, we have identified a commercially available anti-human monoclonal antibody that is able to detect SIRPα of S. sciureus monkeys and that, therefore, can facilitate the study of the immunomodulatory role of SIRPα when S. sciureus is used as a model.

  8. Personality Model in Human Resources Management

    OpenAIRE

    Jovan Zubovic

    2008-01-01

    This paper presents the new „Personality model” of managing human resources in an organisation. The model analyses administrative personnel (usually called management) in an organisation and divides them into three core categories: managers, executives and advisors. Unlike traditional models which do not recognise advisors as part of an organisation, this model gives to advisors the same ranking as managers and executives. Model traces 11 categories of personality traits for every employee, r...

  9. Notch signaling activation in human embryonic stem cells is required for embryonic but not trophoblastic lineage commitment

    OpenAIRE

    Yu, Xiaobing; Zou, Jizhong; Ye, Zhaohui; Hammond, Holly; Chen, Guibin; Tokunaga, Akinori; Mali, Prashant; Li, Yue-Ming; Civin, Curt; Gaiano, Nicholas; Cheng, Linzhao

    2008-01-01

    The Notch signaling pathway plays important roles in cell fate determination during embryonic development and adult life. In this study, we focus on the role of Notch signaling in governing cell fate choices in human embryonic stem (hES) cells. Using genetic and pharmacological approaches, we achieved both blockade and conditional activation of Notch signaling in several hES cell lines. We report here that activation of Notch signaling is required for undifferentiated hES cells to form the pr...

  10. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB.

    Science.gov (United States)

    Sinha, Shriprakash

    2016-12-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d -connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.

  11. Computational Intelligence in a Human Brain Model

    Directory of Open Access Journals (Sweden)

    Viorel Gaftea

    2016-06-01

    Full Text Available This paper focuses on the current trends in brain research domain and the current stage of development of research for software and hardware solutions, communication capabilities between: human beings and machines, new technologies, nano-science and Internet of Things (IoT devices. The proposed model for Human Brain assumes main similitude between human intelligence and the chess game thinking process. Tactical & strategic reasoning and the need to follow the rules of the chess game, all are very similar with the activities of the human brain. The main objective for a living being and the chess game player are the same: securing a position, surviving and eliminating the adversaries. The brain resolves these goals, and more, the being movement, actions and speech are sustained by the vital five senses and equilibrium. The chess game strategy helps us understand the human brain better and easier replicate in the proposed ‘Software and Hardware’ SAH Model.

  12. 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)

  13. Red is not a proxy signal for female genitalia in humans.

    Directory of Open Access Journals (Sweden)

    Sarah E Johns

    Full Text Available Red is a colour that induces physiological and psychological effects in humans, affecting competitive and sporting success, signalling and enhancing male social dominance. The colour is also associated with increased sexual attractiveness, such that women associated with red objects or contexts are regarded as more desirable. It has been proposed that human males have a biological predisposition towards the colour red such that it is 'sexually salient'. This hypothesis argues that women use the colour red to announce impending ovulation and sexual proceptivity, with this functioning as a proxy signal for genital colour, and that men show increased attraction in consequence. In the first test of this hypothesis, we show that contrary to the hypothesis, heterosexual men did not prefer redder female genitalia and, by extension, that red is not a proxy signal for genital colour. We found a relative preference for pinker genital images with redder genitalia rated significantly less sexually attractive. This effect was independent of raters' prior sexual experience and variation in female genital morphology. Our results refute the hypothesis that men's attraction to red is linked to an implied relationship to genital colour and women's signalling of fertility and sexual proceptivity.

  14. Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.

    Directory of Open Access Journals (Sweden)

    Magdalena Angelova

    Full Text Available Human Cytomegalovirus (HCMV is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.

  15. Nitric oxide signaling depends on biotin in Jurkat human lymphoma cells.

    Science.gov (United States)

    Rodriguez-Melendez, Rocio; Zempleni, Janos

    2009-03-01

    Biotin affects gene expression through a diverse array of cell signaling pathways. Previous studies provided evidence that cGMP-dependent signaling also depends on biotin, but the mechanistic sequence of cGMP regulation by biotin is unknown. Here we tested the hypothesis that the effects of biotin in cGMP-dependent cell signaling are mediated by nitric oxide (NO). Human lymphoid (Jurkat) cells were cultured in media containing deficient (0.025 nmol/L), physiological (0.25 nmol/L), and pharmacological (10 nmol/L) concentrations of biotin for 5 wk. Both levels of intracellular biotin and NO exhibited a dose-dependent relationship in regard to biotin concentrations in culture media. Effects of biotin on NO levels were disrupted by the NO synthase (NOS) inhibitor N-monomethyl-arginine. Biotin-dependent production of NO was linked with biotin-dependent expression of endothelial and neuronal NOS, but not inducible NOS. Previous studies revealed that NO is an activator of guanylate cyclase. Consistent with these previous observations, biotin-dependent generation of NO increased the abundance of cGMP in Jurkat cells. Finally, the biotin-dependent generation of cGMP increased protein kinase G activity. Collectively, the results of this study are consistent with the hypothesis that biotin-dependent cGMP signaling in human lymphoid cells is mediated by NO.

  16. Human engineering design considerations for the use of signal color enhancement in ASW displays

    Energy Technology Data Exchange (ETDEWEB)

    Banks, W.W.

    1990-11-01

    The Lawrence Livermore National Laboratory (LLNL) was requested to examine and define man-machine limits as part of the Office of Naval Technology's High Gain Initiative program (HGI). As an initial investigative area, LLNL's Systems and Human Performance effort focused upon color display interfaces and the use of color enhancement techniques to define human and system interface limits in signal detection and discrimination tasks. The knowledgeable and prudent use of color in different types of display is believed to facilitate human visual detection, discrimination and recognition in complex visual tasks. The consideration and understanding of the complex set of interacting variables associated with the prudent use of color is essential to optimize human performance, especially in the ASW community. The designers of advanced display technology and signal processing algorithms may be eventually called upon to present pre-processed information to ASW operators and researchers using the latest color enhancement techniques. These techniques, however, may be limited if one does not understand the complexity and limits of human information processing which reflects the assessed state of knowledge relevant to the use of color in displays. The initial sections of this report discuss various aspects of color presentation and the problems typically encountered, while the last section deals with a specific research proposal required to further our understanding and proper use of color enhancement methods.

  17. Long-Term Expansion, Enhanced Chondrogenic Potential, and Suppression of Endochondral Ossification of Adult Human MSCs via WNT Signaling Modulation

    Directory of Open Access Journals (Sweden)

    Roberto Narcisi

    2015-03-01

    Full Text Available Mesenchymal stem cells (MSCs are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair.

  18. Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways

    OpenAIRE

    Lezhnina, Ksenia; Kovalchuk, Olga; Zhavoronkov, Alexander A.; Korzinkin, Mikhail B.; Zabolotneva, Anastasia A.; Shegay, Peter V.; Sokov, Dmitry G.; Gaifullin, Nurshat M.; Rusakov, Igor G.; Aliper, Alexander M.; Roumiantsev, Sergey A.; Alekseev, Boris Y.; Borisov, Nikolay M.; Buzdin, Anton A.

    2014-01-01

    We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer. Using Illumina HT12v4 microarrays, we profiled gene expression ...

  19. CCR5 Signal Transduction in Macrophages by Human Immunodeficiency Virus and Simian Immunodeficiency Virus Envelopes

    OpenAIRE

    Arthos, James; Rubbert, Andrea; Rabin, Ronald L.; Cicala, Claudia; Machado, Elizabeth; Wildt, Kathryne; Hanbach, Meredith; Steenbeke, Tavis D.; Swofford, Ruth; Farber, Joshua M.; Fauci, Anthony S.

    2000-01-01

    The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1β. Distinct differences in the capacity o...

  20. Animal Models of Human Placentation - A Review

    DEFF Research Database (Denmark)

    Carter, Anthony Michael

    2007-01-01

    This review examines the strengths and weaknesses of animal models of human placentation and pays particular attention to the mouse and non-human primates. Analogies can be drawn between mouse and human in placental cell types and genes controlling placental development. There are, however...... and delivers poorly developed young. Guinea pig is a good alternative rodent model and among the few species known to develop pregnancy toxaemia. The sheep is well established as a model in fetal physiology but is of limited value for placental research. The ovine placenta is epitheliochorial...... and endometrium is similar in macaques and baboons, as is the subsequent lacunar stage. The absence of interstitial trophoblast cells in the monkey is an important difference from human placentation. However, there is a strong resemblance in the way spiral arteries are invaded and transformed in the macaque...

  1. Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation.

    Science.gov (United States)

    Ambhore, Nilesh Sudhakar; Katragadda, Rathnavali; Raju Kalidhindi, Rama Satyanarayana; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S; Sathish, Venkatachalem

    2018-04-20

    Airway smooth muscle (ASM) cell hyperplasia driven by persistent inflammation is a hallmark feature of remodeling in asthma. Sex steroid signaling in the lungs is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men. Our previous studies demonstrated that estrogen receptor (ER) expression increases in asthmatic human ASM; however, very limited data are available regarding differential roles of ERα vs. ERβ isoforms in human ASM cell proliferation. In this study, we evaluated the effect of selective ERα and ERβ modulators on platelet-derived growth factor (PDGF)-stimulated ASM proliferation and the mechanisms involved. Asthmatic and non-asthmatic primary human ASM cells were treated with PDGF, 17β-estradiol, ERα-agonist and/or ERβ-agonist and/or G-protein-coupled estrogen receptor 30 (GPR30/GPER) agonist and proliferation was measured using MTT and CyQuant assays followed by cell cycle analysis. Transfection of small interfering RNA (siRNA) ERα and ERβ significantly altered the human ASM proliferation. The specificity of siRNA transfection was confirmed by Western blot analysis. Gene and protein expression of cell cycle-related antigens (PCNA and Ki67) and C/EBP were measured by RT-PCR and Western analysis, along with cell signaling proteins. PDGF significantly increased ASM proliferation in non-asthmatic and asthmatic cells. Treatment with PPT showed no significant effect on PDGF-induced proliferation, whereas WAY interestingly suppressed proliferation via inhibition of ERK1/2, Akt, and p38 signaling. PDGF-induced gene expression of PCNA, Ki67 and C/EBP in human ASM was significantly lower in cells pre-treated with WAY. Furthermore, WAY also inhibited PDGF-activated PCNA, C/EBP, cyclin-D1, and cyclin-E. Overall, we demonstrate ER isoform-specific signaling in the context of ASM proliferation. Activation of ERβ can diminish remodeling in human ASM by inhibiting pro-proliferative signaling pathways

  2. A Multi-Model Stereo Similarity Function Based on Monogenic Signal Analysis in Poisson Scale Space

    Directory of Open Access Journals (Sweden)

    Jinjun Li

    2011-01-01

    Full Text Available A stereo similarity function based on local multi-model monogenic image feature descriptors (LMFD is proposed to match interest points and estimate disparity map for stereo images. Local multi-model monogenic image features include local orientation and instantaneous phase of the gray monogenic signal, local color phase of the color monogenic signal, and local mean colors in the multiscale color monogenic signal framework. The gray monogenic signal, which is the extension of analytic signal to gray level image using Dirac operator and Laplace equation, consists of local amplitude, local orientation, and instantaneous phase of 2D image signal. The color monogenic signal is the extension of monogenic signal to color image based on Clifford algebras. The local color phase can be estimated by computing geometric product between the color monogenic signal and a unit reference vector in RGB color space. Experiment results on the synthetic and natural stereo images show the performance of the proposed approach.

  3. Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

    International Nuclear Information System (INIS)

    Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas; Astorga-Wells, Juan; Zubarev, Roman A.; Del Campo, Mark; Criswell, Angela R.; Sanctis, Daniele de; Jovine, Luca; Toftgård, Rune

    2013-01-01

    Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics

  4. Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

    Energy Technology Data Exchange (ETDEWEB)

    Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden); Astorga-Wells, Juan [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Biomotif AB, Enhagsvägen 7, SE-182 12 Danderyd (Sweden); Zubarev, Roman A. [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Del Campo, Mark; Criswell, Angela R. [Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States); Sanctis, Daniele de [European Synchrotron Radiation Facility, 6 Rue Jules Horowitz, 38043 Grenoble (France); Jovine, Luca, E-mail: luca.jovine@ki.se; Toftgård, Rune, E-mail: luca.jovine@ki.se [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden)

    2013-12-01

    Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

  5. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

    Directory of Open Access Journals (Sweden)

    Leilei Zhong

    2015-08-01

    Full Text Available Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA. Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP/Transforming growth factor-β (TGFβ, Parathyroid hormone-related peptide (PTHrP, Indian hedgehog (IHH, Fibroblast growth factor (FGF, Insulin like growth factor (IGF and Hypoxia-inducible factor (HIF. This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC repair, and improves understanding of the disease stages and cellular responses within an OA articular joint.

  6. Quantitative Analysis of Signaling Networks across Differentially Embedded Tumors Highlights Interpatient Heterogeneity in Human Glioblastoma

    Science.gov (United States)

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor, with a dismal mean survival even with the current standard of care. Although in vitro cell systems can provide mechanistic insight into the regulatory networks governing GBM cell proliferation and migration, clinical samples provide a more physiologically relevant view of oncogenic signaling networks. However, clinical samples are not widely available and may be embedded for histopathologic analysis. With the goal of accurately identifying activated signaling networks in GBM tumor samples, we investigated the impact of embedding in optimal cutting temperature (OCT) compound followed by flash freezing in LN2 vs immediate flash freezing (iFF) in LN2 on protein expression and phosphorylation-mediated signaling networks. Quantitative proteomic and phosphoproteomic analysis of 8 pairs of tumor specimens revealed minimal impact of the different sample processing strategies and highlighted the large interpatient heterogeneity present in these tumors. Correlation analyses of the differentially processed tumor sections identified activated signaling networks present in selected tumors and revealed the differential expression of transcription, translation, and degradation associated proteins. This study demonstrates the capability of quantitative mass spectrometry for identification of in vivo oncogenic signaling networks from human tumor specimens that were either OCT-embedded or immediately flash-frozen. PMID:24927040

  7. Signal Quality Improvement Algorithms for MEMS Gyroscope-Based Human Motion Analysis Systems: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Jiaying Du

    2018-04-01

    Full Text Available Motion sensors such as MEMS gyroscopes and accelerometers are characterized by a small size, light weight, high sensitivity, and low cost. They are used in an increasing number of applications. However, they are easily influenced by environmental effects such as temperature change, shock, and vibration. Thus, signal processing is essential for minimizing errors and improving signal quality and system stability. The aim of this work is to investigate and present a systematic review of different signal error reduction algorithms that are used for MEMS gyroscope-based motion analysis systems for human motion analysis or have the potential to be used in this area. A systematic search was performed with the search engines/databases of the ACM Digital Library, IEEE Xplore, PubMed, and Scopus. Sixteen papers that focus on MEMS gyroscope-related signal processing and were published in journals or conference proceedings in the past 10 years were found and fully reviewed. Seventeen algorithms were categorized into four main groups: Kalman-filter-based algorithms, adaptive-based algorithms, simple filter algorithms, and compensation-based algorithms. The algorithms were analyzed and presented along with their characteristics such as advantages, disadvantages, and time limitations. A user guide to the most suitable signal processing algorithms within this area is presented.

  8. Signal Quality Improvement Algorithms for MEMS Gyroscope-Based Human Motion Analysis Systems: A Systematic Review.

    Science.gov (United States)

    Du, Jiaying; Gerdtman, Christer; Lindén, Maria

    2018-04-06

    Motion sensors such as MEMS gyroscopes and accelerometers are characterized by a small size, light weight, high sensitivity, and low cost. They are used in an increasing number of applications. However, they are easily influenced by environmental effects such as temperature change, shock, and vibration. Thus, signal processing is essential for minimizing errors and improving signal quality and system stability. The aim of this work is to investigate and present a systematic review of different signal error reduction algorithms that are used for MEMS gyroscope-based motion analysis systems for human motion analysis or have the potential to be used in this area. A systematic search was performed with the search engines/databases of the ACM Digital Library, IEEE Xplore, PubMed, and Scopus. Sixteen papers that focus on MEMS gyroscope-related signal processing and were published in journals or conference proceedings in the past 10 years were found and fully reviewed. Seventeen algorithms were categorized into four main groups: Kalman-filter-based algorithms, adaptive-based algorithms, simple filter algorithms, and compensation-based algorithms. The algorithms were analyzed and presented along with their characteristics such as advantages, disadvantages, and time limitations. A user guide to the most suitable signal processing algorithms within this area is presented.

  9. Human CD180 Transmits Signals via the PIM-1L Kinase.

    Directory of Open Access Journals (Sweden)

    Nicole Egli

    Full Text Available Toll-like receptors (TLRs are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a downstream signaling cascade. The CD180/MD1 molecular complex is an unusual member of the TLR family, since it lacks the components that are normally required for signal transduction by other TLRs. Therefore the CD180/MD 1 complex has been considered of being incapable of independently initiating cellular signals. Using chemogenetic approaches we identified specifically the membrane bound long form of PIM-1 kinase, PIM-1L as the mediator of CD180-dependent signaling. A dominant negative isoform of PIM-1L, but not of other PIM kinases, inhibited signaling elicited by cross-linking of CD180, and this effect was phenocopied by PIM inhibitors. PIM-1L was directed to the cell membrane by its N-terminal extension, where it colocalized and physically associated with CD180. Triggering CD180 also induced increased phosphorylation of the anti-apoptotic protein BAD in a PIM kinase-dependent fashion. Also in primary human B cells, which are the main cells expressing CD180 in man, cross-linking of CD180 by monoclonal antibodies stimulated cell survival and proliferation that was abrogated by specific inhibitors. By associating with PIM-1L, CD180 can thus obtain autonomous signaling capabilities, and this complex is then channeling inflammatory signals into B cell survival programs. Pharmacological inhibition of PIM-1 should therefore provide novel therapeutic options in diseases that respond to innate immune stimulation with subsequently increased B cell activity, such as lupus erythematosus or myasthenia gravis.

  10. A statistical model of future human actions

    International Nuclear Information System (INIS)

    Woo, G.

    1992-02-01

    A critical review has been carried out of models of future human actions during the long term post-closure period of a radioactive waste repository. Various Markov models have been considered as alternatives to the standard Poisson model, and the problems of parameterisation have been addressed. Where the simplistic Poisson model unduly exaggerates the intrusion risk, some form of Markov model may have to be introduced. This situation may well arise for shallow repositories, but it is less likely for deep repositories. Recommendations are made for a practical implementation of a computer based model and its associated database. (Author)

  11. EEG Signal Classification With Super-Dirichlet Mixture Model

    DEFF Research Database (Denmark)

    Ma, Zhanyu; Tan, Zheng-Hua; Prasad, Swati

    2012-01-01

    Classification of the Electroencephalogram (EEG) signal is a challengeable task in the brain-computer interface systems. The marginalized discrete wavelet transform (mDWT) coefficients extracted from the EEG signals have been frequently used in researches since they reveal features related...

  12. A Model of the Human Eye

    Science.gov (United States)

    Colicchia, G.; Wiesner, H.; Waltner, C.; Zollman, D.

    2008-01-01

    We describe a model of the human eye that incorporates a variable converging lens. The model can be easily constructed by students with low-cost materials. It shows in a comprehensible way the functionality of the eye's optical system. Images of near and far objects can be focused. Also, the defects of near and farsighted eyes can be demonstrated.

  13. Models of the Human in Tantric Hinduism

    DEFF Research Database (Denmark)

    Olesen, Bjarne Wernicke; Flood, Gavin

    2019-01-01

    This research project explores the origins, developments and transformations of yogic models of the human (e.g. kuṇḍalinī yoga, the cakra system and ritual sex) in the tantric goddess traditions or what might be called Śāktism of medieval India. These Śākta models of esoteric anatomy originating...

  14. Modeling human learning involved in car driving

    NARCIS (Netherlands)

    Wewerinke, P.H.

    1994-01-01

    In this paper, car driving is considered at the level of human tracking and maneuvering in the context of other traffic. A model analysis revealed the most salient features determining driving performance and safety. Learning car driving is modelled based on a system theoretical approach and based

  15. Mathematical human body modelling for impact loading

    NARCIS (Netherlands)

    Happee, R.; Morsink, P.L.J.; Wismans, J.S.H.M.

    1999-01-01

    Mathematical modelling of the human body is widely used for automotive crash safety research and design. Simulations have contributed to a reduction of injury numbers by optimisation of vehicle structures and restraint systems. Currently such simulations are largely performed using occupant models

  16. Dressed for Sex: Red as a Female Sexual Signal in Humans

    Science.gov (United States)

    Elliot, Andrew J.; Pazda, Adam D.

    2012-01-01

    Background In many non-human primate species, a display of red by a female serves as a sexual signal to attract male conspecifics. Red is associated with sex and romance in humans, and women convey their sexual interest to men through a variety of verbal, postural, and behavioral means. In the present research, we investigate whether female red ornamentation in non-human primates has a human analog, whereby women use a behavioral display of red to signal their sexual interest to men. Methodology/Principal Findings Three studies tested the hypothesis that women use red clothing to communicate sexual interest to men in profile pictures on dating websites. In Study 1, women who imagined being interested in casual sex were more likely to display red (but not other colors) on their anticipated web profile picture. In Study 2, women who indicated interest in casual sex were more likely to prominently display red (but not other colors) on their actual web profile picture. In Study 3, women on a website dedicated to facilitating casual sexual relationships were more likely to prominently exhibit red (but not other colors) than women on a website dedicated to facilitating marital relationships. Conclusions/Significance These results establish a provocative parallel between women and non-human female primates in red signal coloration in the mating game. This research shows, for the first time, a functional use of color in women's sexual self-presentation, and highlights the need to extend research on color beyond physics, physiology, and preference to psychological functioning. PMID:22514643

  17. Dressed for sex: red as a female sexual signal in humans.

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    Andrew J Elliot

    Full Text Available BACKGROUND: In many non-human primate species, a display of red by a female serves as a sexual signal to attract male conspecifics. Red is associated with sex and romance in humans, and women convey their sexual interest to men through a variety of verbal, postural, and behavioral means. In the present research, we investigate whether female red ornamentation in non-human primates has a human analog, whereby women use a behavioral display of red to signal their sexual interest to men. METHODOLOGY/PRINCIPAL FINDINGS: Three studies tested the hypothesis that women use red clothing to communicate sexual interest to men in profile pictures on dating websites. In Study 1, women who imagined being interested in casual sex were more likely to display red (but not other colors on their anticipated web profile picture. In Study 2, women who indicated interest in casual sex were more likely to prominently display red (but not other colors on their actual web profile picture. In Study 3, women on a website dedicated to facilitating casual sexual relationships were more likely to prominently exhibit red (but not other colors than women on a website dedicated to facilitating marital relationships. CONCLUSIONS/SIGNIFICANCE: These results establish a provocative parallel between women and non-human female primates in red signal coloration in the mating game. This research shows, for the first time, a functional use of color in women's sexual self-presentation, and highlights the need to extend research on color beyond physics, physiology, and preference to psychological functioning.

  18. Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model

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    Sadia Benamrouz

    2014-06-01

    Full Text Available Cryptosporidium species are apicomplexan protozoans that are found worldwide. These parasites constitute a large risk to human and animal health. They cause self-limited diarrhea in immunocompetent hosts and a life-threatening disease in immunocompromised hosts. Interestingly, Cryptosporidium parvum has been related to digestive carcinogenesis in humans. Consistent with a potential tumorigenic role of this parasite, in an original reproducible animal model of chronic cryptosporidiosis based on dexamethasone-treated or untreated adult SCID mice, we formerly reported that C. parvum (strains of animal and human origin is able to induce digestive adenocarcinoma even in infections induced with very low inoculum. The aim of this study was to further characterize this animal model and to explore metabolic pathways potentially involved in the development of C. parvum-induced ileo-caecal oncogenesis. We searched for alterations in genes or proteins commonly involved in cell cycle, differentiation or cell migration, such as β-catenin, Apc, E-cadherin, Kras and p53. After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53. Mutations in the selected loci of studied genes were not found after high-throughput sequencing. Furthermore, alterations in the ultrastructure of adherens junctions of the ileo-caecal neoplastic epithelia of C. parvum-infected mice were recorded using transmission electron microscopy. In conclusion, we found for the first time that the Wnt signaling pathway, and particularly the cytoskeleton network, seems to be pivotal for the development of the C. parvum-induced neoplastic process and cell migration of transformed cells. Furthermore, this model is a valuable tool in understanding the host-pathogen interactions associated with the intricate infection process of this parasite, which is able to modulate host cytoskeleton activities and several host

  19. Human butyrylcholinesterase polymorphism: Molecular modeling.

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    Lushchekina, S; Delacour, H; Lockridge, O; Masson, P

    2015-01-01

    Prolonged apnoea following injection of ester-containing myoralaxants was first described in 1953. Because a large part of administered succinylcholine is shortly hydrolyzed by plasma butyrylcholinesterase (BChE) under normal conditions, prolonged apnoea was attributed to deficiency in BChE. It was found that BChE deficiency was due to genetic variations. Human BChE gene shows a large polyallelism. About 75 natural mutations of the BCHE gene have been documented so far [1]. Most of them cause alteration in BChE activity through point mutation effect on catalytic activity. Frame shifts and stop codons may also affect expression, or cause truncations in the sequence. Recently, two novel BChE "silent" variants, Val204Asp [2] and Ala34Val [3], causing prolonged neuromuscular block after administration of mivacurium, were discovered. Mutations were genetically and kinetically characterized. The aim of the current study was to understand how these mutations determine "silent" phenotype. Molecular dynamics studies were carried out with NAMD 2.9 software at the Lomonosov supercomputer. Charmm 36 force field was used, periodical boundary conditions, 1 atm pressure, 298 K. 100 ns molecular dynamics runs were performed for the wild-type BChE and its mutants Val204Asp and Ala34Val. Unlike wild-type BChE, which retained its operative catalytic triad through the whole MD simulation, the catalytic triad of mutants was disrupted, making chemical step impossible. Val204Asp mutation leads to reorganization of hydrogen bonding network around the catalytic triad, which in turn increases the distance between catalytic residue main chains. Mutation Ala34Val, located on the protein surface, leads to increased fluctuations in the Ω-loop and subsequent disruption of the gorge structure, including disruption of the catalytic triad and formation of new hydrogen bonds involving catalytic center residues. Comparative study of the "silent" Ala328Asp mutant and the catalytically active mutant

  20. Humanized Mouse Models of Staphylococcus aureus Infection

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    Dane Parker

    2017-05-01

    Full Text Available Staphylococcus aureus is a successful human pathogen that has adapted itself in response to selection pressure by the human immune system. A commensal of the human skin and nose, it is a leading cause of several conditions: skin and soft tissue infection, pneumonia, septicemia, peritonitis, bacteremia, and endocarditis. Mice have been used extensively in all these conditions to identify virulence factors and host components important for pathogenesis. Although significant effort has gone toward development of an anti-staphylococcal vaccine, antibodies have proven ineffective in preventing infection in humans after successful studies in mice. These results have raised questions as to the utility of mice to predict patient outcome and suggest that humanized mice might prove useful in modeling infection. The development of humanized mouse models of S. aureus infection will allow us to assess the contribution of several human-specific virulence factors, in addition to exploring components of the human immune system in protection against S. aureus infection. Their use is discussed in light of several recently reported studies.

  1. The truthful signalling hypothesis: an explicit general equilibrium model.

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    Hausken, Kjell; Hirshleifer, Jack

    2004-06-21

    In mating competition, the truthful signalling hypothesis (TSH), sometimes known as the handicap principle, asserts that higher-quality males signal while lower-quality males do not (or else emit smaller signals). Also, the signals are "believed", that is, females mate preferentially with higher-signalling males. Our analysis employs specific functional forms to generate analytic solutions and numerical simulations that illuminate the conditions needed to validate the TSH. Analytic innovations include: (1) A Mating Success Function indicates how female mating choices respond to higher and lower signalling levels. (2) A congestion function rules out corner solutions in which females would mate exclusively with higher-quality males. (3) A Malthusian condition determines equilibrium population size as related to per-capita resource availability. Equilibria validating the TSH are achieved over a wide range of parameters, though not universally. For TSH equilibria it is not strictly necessary that the high-quality males have an advantage in terms of lower per-unit signalling costs, but a cost difference in favor of the low-quality males cannot be too great if a TSH equilibrium is to persist. And although the literature has paid less attention to these points, TSH equilibria may also fail if: the quality disparity among males is too great, or the proportion of high-quality males in the population is too large, or if the congestion effect is too weak. Signalling being unprofitable in aggregate, it can take off from a no-signalling equilibrium only if the trait used for signalling is not initially a handicap, but instead is functionally useful at low levels. Selection for this trait sets in motion a bandwagon, whereby the initially useful indicator is pushed by male-male competition into the domain where it does indeed become a handicap.

  2. Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: state of the art after 25 years.

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    Engelberg, David; Perlman, Riki; Levitzki, Alexander

    2014-12-01

    In the very first article that appeared in Cellular Signalling, published in its inaugural issue in October 1989, we reviewed signal transduction pathways in Saccharomyces cerevisiae. Although this yeast was already a powerful model organism for the study of cellular processes, it was not yet a valuable instrument for the investigation of signaling cascades. In 1989, therefore, we discussed only two pathways, the Ras/cAMP and the mating (Fus3) signaling cascades. The pivotal findings concerning those pathways undoubtedly contributed to the realization that yeast is a relevant model for understanding signal transduction in higher eukaryotes. Consequently, the last 25 years have witnessed the discovery of many signal transduction pathways in S. cerevisiae, including the high osmotic glycerol (Hog1), Stl2/Mpk1 and Smk1 mitogen-activated protein (MAP) kinase pathways, the TOR, AMPK/Snf1, SPS, PLC1 and Pkr/Gcn2 cascades, and systems that sense and respond to various types of stress. For many cascades, orthologous pathways were identified in mammals following their discovery in yeast. Here we review advances in the understanding of signaling in S. cerevisiae over the last 25 years. When all pathways are analyzed together, some prominent themes emerge. First, wiring of signaling cascades may not be identical in all S. cerevisiae strains, but is probably specific to each genetic background. This situation complicates attempts to decipher and generalize these webs of reactions. Secondly, the Ras/cAMP and the TOR cascades are pivotal pathways that affect all processes of the life of the yeast cell, whereas the yeast MAP kinase pathways are not essential. Yeast cells deficient in all MAP kinases proliferate normally. Another theme is the existence of central molecular hubs, either as single proteins (e.g., Msn2/4, Flo11) or as multisubunit complexes (e.g., TORC1/2), which are controlled by numerous pathways and in turn determine the fate of the cell. It is also apparent that

  3. Insulin Signaling, Resistance, and the Metabolic Syndrome: Insights from Mouse Models to Disease Mechanisms

    Science.gov (United States)

    Guo, Shaodong

    2014-01-01

    Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1. PMID:24281010

  4. BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis.

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    Childs, Andrew J; Kinnell, Hazel L; Collins, Craig S; Hogg, Kirsten; Bayne, Rosemary A L; Green, Samira J; McNeilly, Alan S; Anderson, Richard A

    2010-08-01

    Primordial germ cells (PGCs) are the embryonic precursors of gametes in the adult organism, and their development, differentiation, and survival are regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human PGC niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the bone morphogenetic protein (BMP) signaling apparatus in the human fetal ovary, from postmigratory PGC proliferation to the onset of primordial follicle formation. We find developmentally regulated and reciprocal patterns of expression of BMP2 and BMP4 and identify germ cells to be the exclusive targets of ovarian BMP signaling. By establishing long-term cultures of human fetal ovaries in which PGCs are retained within their physiological niche, we find that BMP4 negatively regulates postmigratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both muscle segment homeobox (MSX)1 and MSX2 in the human fetal ovary and reveal a selective upregulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells.

  5. Sequential Markov chain Monte Carlo filter with simultaneous model selection for electrocardiogram signal modeling.

    Science.gov (United States)

    Edla, Shwetha; Kovvali, Narayan; Papandreou-Suppappola, Antonia

    2012-01-01

    Constructing statistical models of electrocardiogram (ECG) signals, whose parameters can be used for automated disease classification, is of great importance in precluding manual annotation and providing prompt diagnosis of cardiac diseases. ECG signals consist of several segments with different morphologies (namely the P wave, QRS complex and the T wave) in a single heart beat, which can vary across individuals and diseases. Also, existing statistical ECG models exhibit a reliance upon obtaining a priori information from the ECG data by using preprocessing algorithms to initialize the filter parameters, or to define the user-specified model parameters. In this paper, we propose an ECG modeling technique using the sequential Markov chain Monte Carlo (SMCMC) filter that can perform simultaneous model selection, by adaptively choosing from different representations depending upon the nature of the data. Our results demonstrate the ability of the algorithm to track various types of ECG morphologies, including intermittently occurring ECG beats. In addition, we use the estimated model parameters as the feature set to classify between ECG signals with normal sinus rhythm and four different types of arrhythmia.

  6. Mapping glucose-mediated gut-to-brain signalling pathways in humans.

    Science.gov (United States)

    Little, Tanya J; McKie, Shane; Jones, Richard B; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G; McLaughlin, John T

    2014-08-01

    Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. Copyright © 2014. Published by Elsevier Inc.

  7. Developmental changes of BOLD signal correlations with global human EEG power and synchronization during working memory.

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    Lars Michels

    Full Text Available In humans, theta band (5-7 Hz power typically increases when performing cognitively demanding working memory (WM tasks, and simultaneous EEG-fMRI recordings have revealed an inverse relationship between theta power and the BOLD (blood oxygen level dependent signal in the default mode network during WM. However, synchronization also plays a fundamental role in cognitive processing, and the level of theta and higher frequency band synchronization is modulated during WM. Yet, little is known about the link between BOLD, EEG power, and EEG synchronization during WM, and how these measures develop with human brain maturation or relate to behavioral changes. We examined EEG-BOLD signal correlations from 18 young adults and 15 school-aged children for age-dependent effects during a load-modulated Sternberg WM task. Frontal load (in-dependent EEG theta power was significantly enhanced in children compared to adults, while adults showed stronger fMRI load effects. Children demonstrated a stronger negative correlation between global theta power and the BOLD signal in the default mode network relative to adults. Therefore, we conclude that theta power mediates the suppression of a task-irrelevant network. We further conclude that children suppress this network even more than adults, probably from an increased level of task-preparedness to compensate for not fully mature cognitive functions, reflected in lower response accuracy and increased reaction time. In contrast to power, correlations between instantaneous theta global field synchronization and the BOLD signal were exclusively positive in both age groups but only significant in adults in the frontal-parietal and posterior cingulate cortices. Furthermore, theta synchronization was weaker in children and was--in contrast to EEG power--positively correlated with response accuracy in both age groups. In summary we conclude that theta EEG-BOLD signal correlations differ between spectral power and

  8. Calcium Imaging of Nerve-Mast Cell Signaling in the Human Intestine

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    Sabine Buhner

    2017-11-01

    Full Text Available Introduction: It is suggested that an altered microenvironment in the gut wall alters communication along a mast cell nerve axis. We aimed to record for the first time signaling between mast cells and neurons in intact human submucous preparations.Methods: We used the Ca2+ sensitive dye Fluo-4 AM to simultaneously image changes in intracellular calcium [Ca+2]i (%ΔF/F in neurons and mast cells. Data are presented as median with interquartile ranges (25/75%.Results: We recorded nerve responses in 29 samples upon selective activation of 223 mast cells by IgE receptor cross linking with the antibody mAb22E7. Mast cells responded to mAb22E7 with a median [Ca+2]i increase of 20% (11/39 peaking 90 s (64/144 after the application. Only very few neurons responded and the median percentage of responding neuronal area was 0% (0/5.9. Mast cell activation remained in the presence of the fast sodium channel blocker tetrodotoxin. Specific neuronal activation by transmural electrical field stimulation (EFS in 34 samples evoked instantaneously [Ca+2]i signals in submucous neurons. This was followed by a [Ca+2]i peak response of 8%ΔF/F (4/15 in 33% of 168 mast cells in the field of view. The mast cell response was abolished by the nerve blocker tetrododoxin, reduced by the Calcitonin Gene-Related Peptide receptor 1 antagonist BIBN-4096 and the Vasoactive Intestinal Peptide receptor antagonist PG97-269, but not by blockade of the neurokinin receptors 1–3.Conclusion: The findings revealed bidirectional signaling between mast cells and submucous neurons in human gut. In our macroscopically normal preparations a nerve to mast cell signaling was very prominent whereas a mast cell to nerve signaling was rather rare.

  9. Human models of acute lung injury

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    Alastair G. Proudfoot

    2011-03-01

    Full Text Available Acute lung injury (ALI is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

  10. Conceptual modelling of human resource evaluation process

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    Negoiţă Doina Olivia

    2017-01-01

    Full Text Available Taking into account the highly diverse tasks which employees have to fulfil due to complex requirements of nowadays consumers, the human resource within an enterprise has become a strategic element for developing and exploiting products which meet the market expectations. Therefore, organizations encounter difficulties when approaching the human resource evaluation process. Hence, the aim of the current paper is to design a conceptual model of the aforementioned process, which allows the enterprises to develop a specific methodology. In order to design the conceptual model, Business Process Modelling instruments were employed - Adonis Community Edition Business Process Management Toolkit using the ADONIS BPMS Notation. The conceptual model was developed based on an in-depth secondary research regarding the human resource evaluation process. The proposed conceptual model represents a generic workflow (sequential and/ or simultaneously activities, which can be extended considering the enterprise’s needs regarding their requirements when conducting a human resource evaluation process. Enterprises can benefit from using software instruments for business process modelling as they enable process analysis and evaluation (predefined / specific queries and also model optimization (simulations.

  11. Construction and Deciphering of Human Phosphorylation-Mediated Signaling Transduction Networks.

    Science.gov (United States)

    Zhang, Menghuan; Li, Hong; He, Ying; Sun, Han; Xia, Li; Wang, Lishun; Sun, Bo; Ma, Liangxiao; Zhang, Guoqing; Li, Jing; Li, Yixue; Xie, Lu

    2015-07-02

    Protein phosphorylation is the most abundant reversible covalent modification. Human protein kinases participate in almost all biological pathways, and approximately half of the kinases are associated with disease. PhoSigNet was designed to store and display human phosphorylation-mediated signal transduction networks, with additional information related to cancer. It contains 11 976 experimentally validated directed edges and 216 871 phosphorylation sites. Moreover, 3491 differentially expressed proteins in human cancer from dbDEPC, 18 907 human cancer variation sites from CanProVar, and 388 hyperphosphorylation sites from PhosphoSitePlus were collected as annotation information. Compared with other phosphorylation-related databases, PhoSigNet not only takes the kinase-substrate regulatory relationship pairs into account, but also extends regulatory relationships up- and downstream (e.g., from ligand to receptor, from G protein to kinase, and from transcription factor to targets). Furthermore, PhoSigNet allows the user to investigate the impact of phosphorylation modifications on cancer. By using one set of in-house time series phosphoproteomics data, the reconstruction of a conditional and dynamic phosphorylation-mediated signaling network was exemplified. We expect PhoSigNet to be a useful database and analysis platform benefiting both proteomics and cancer studies.

  12. A DESIGN FRAMEWORK FOR HUMAN EMOTION RECOGNITION USING ELECTROCARDIOGRAM AND SKIN CONDUCTANCE RESPONSE SIGNALS

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    KHAIRUN NISA’ MINHAD

    2017-11-01

    Full Text Available Identification of human emotional state while driving a vehicle can help in understanding the human behaviour. Based on this identification, a response system can be developed in order to mitigate the impact that may be resulted from the behavioural changes. However, the adaptation of emotions to the environment at most scenarios is subjective to an individual’s perspective. Many factors, mainly cultural and geography, gender, age, life style and history, level of education and professional status, can affect the detection of human emotional affective states. This work investigated sympathetic responses toward human emotions defined by using electrocardiography (ECG and skin conductance response (SCR signals recorded simultaneously. This work aimed to recognize ECG and SCR patterns of the investigated emotions measured using selected sensor. A pilot study was conducted to evaluate the proposed framework. Initial results demonstrated the importance of suitability of the stimuli used to evoke the emotions and high opportunity for the ECG and SCR signals to be used in the automotive real-time emotion recognition systems.

  13. Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

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    Jin Qi

    2017-08-01

    Full Text Available Background/Aims: Mesenchymal stem/stromal cells (MSCs are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. Methods: MSCs derived from human bone marrow (hBMSCs were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63 and gastric cancer (SGC7901 cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. Results: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. Conclusion: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs-derived exosomes induced tumor progression.

  14. Interleukin-1 Acts via the JNK-2 Signaling Pathway to Induce Aggrecan Degradation by Human Chondrocytes.

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    Ismail, Heba M; Yamamoto, Kazuhiro; Vincent, Tonia L; Nagase, Hideaki; Troeberg, Linda; Saklatvala, Jeremy

    2015-07-01

    Aggrecan enables articular cartilage to bear load and resist compression. Aggrecan loss occurs early in osteoarthritis and rheumatoid arthritis and can be induced by inflammatory cytokines such as interleukin-1 (IL-1). IL-1 induces cleavage of specific aggrecans characteristic of the ADAMTS proteinases. The aim of this study was to identify the intracellular signaling pathways by which IL-1 causes aggrecan degradation by human chondrocytes and to investigate how aggrecanase activity is controlled by chondrocytes. We developed a cell-based assay combining small interfering RNA (siRNA)-induced knockdown with aggrecan degradation assays. Human articular chondrocytes were overlaid with bovine aggrecan after transfection with siRNAs against molecules of the IL-1 signaling pathway. After IL-1 stimulation, released aggrecan fragments were detected with AGEG and ARGS neoepitope antibodies. Aggrecanase activity and tissue inhibitor of metalloproteinases 3 levels were measured by enzyme-linked immunosorbent assay. Low-density lipoprotein receptor-related protein 1 (LRP-1) shedding was analyzed by Western blotting. ADAMTS-5 is a major aggrecanase in human chondrocytes, regulating aggrecan degradation in response to IL-1. The tumor necrosis factor receptor-associated 6 (TRAF-6)/transforming growth factor β-activated kinase 1 (TAK-1)/MKK-4 signaling axis is essential for IL-1-induced aggrecan degradation, while NF-κB is not. Of the 3 MAPKs (ERK, p38, and JNK), only JNK-2 showed a significant role in aggrecan degradation. Chondrocytes constitutively secreted aggrecanase, which was continuously endocytosed by LRP-1, keeping the extracellular level of aggrecanase low. IL-1 induced aggrecanase activity in the medium in a JNK-2-dependent manner, possibly by reducing aggrecanase endocytosis, because IL-1 caused JNK-2-dependent shedding of LRP-1. The signaling axis TRAF-6/TAK-1/MKK-4/JNK-2 mediates IL-1-induced aggrecanolysis. The level of aggrecanase is controlled by its

  15. CIRCADIAN REGULATION METABOLIC SIGNALING MECHANISMS OF HUMAN BREAST CANCER GROWTH BY THE NOCTURNAL MELATONIN SIGNAL AND THE CONSEQUENCES OF ITS DISRUPTION BY LIGHT AT NIGHT

    Science.gov (United States)

    Blask, David E.; Hill, Steven M.; Dauchy, Robert T.; Xiang, Shulin; Yuan, Lin; Duplessis, Tamika; Mao, Lulu; Dauchy, Erin; Sauer, Leonard A.

    2011-01-01

    This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light-at-night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. PMID:21605163

  16. Advanced radar detection schemes under mismatched signal models

    CERN Document Server

    Bandiera, Francesco

    2009-01-01

    Adaptive detection of signals embedded in correlated Gaussian noise has been an active field of research in the last decades. This topic is important in many areas of signal processing such as, just to give some examples, radar, sonar, communications, and hyperspectral imaging. Most of the existing adaptive algorithms have been designed following the lead of the derivation of Kelly's detector which assumes perfect knowledge of the target steering vector. However, in realistic scenarios, mismatches are likely to occur due to both environmental and instrumental factors. When a mismatched signal

  17. Ghost-in-the-Machine reveals human social signals for human-robot interaction.

    Science.gov (United States)

    Loth, Sebastian; Jettka, Katharina; Giuliani, Manuel; de Ruiter, Jan P

    2015-01-01

    We used a new method called "Ghost-in-the-Machine" (GiM) to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognize the intentions of customers on the basis of the output of the robotic recognizers. Specifically, we measured which recognizer modalities (e.g., speech, the distance to the bar) were relevant at different stages of the interaction. This provided insights into human social behavior necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognizers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognizers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer's requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human-robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience.

  18. Systematic Analysis of Video Data from Different Human-Robot Interaction Studies: A Categorisation of Social Signals During Error Situations

    OpenAIRE

    Manuel eGiuliani; Nicole eMirnig; Gerald eStollnberger; Susanne eStadler; Roland eBuchner; Manfred eTscheligi

    2015-01-01

    Human?robot interactions are often affected by error situations that are caused by either the robot or the human. Therefore, robots would profit from the ability to recognize when error situations occur. We investigated the verbal and non-verbal social signals that humans show when error situations occur in human?robot interaction experiments. For that, we analyzed 201 videos of five human?robot interaction user studies with varying tasks from four independent projects. The analysis shows tha...

  19. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

    International Nuclear Information System (INIS)

    Dontu, Gabriela; Jackson, Kyle W; McNicholas, Erin; Kawamura, Mari J; Abdallah, Wissam M; Wicha, Max S

    2004-01-01

    suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells

  20. Mouse Chromosome Engineering for Modeling Human Disease

    OpenAIRE

    van der Weyden, Louise; Bradley, Allan

    2006-01-01

    Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the e...

  1. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  2. Enhancement of speech signals - with a focus on voiced speech models

    DEFF Research Database (Denmark)

    Nørholm, Sidsel Marie

    This thesis deals with speech enhancement, i.e., noise reduction in speech signals. This has applications in, e.g., hearing aids and teleconference systems. We consider a signal-driven approach to speech enhancement where a model of the speech is assumed and filters are generated based...... on this model. The basic model used in this thesis is the harmonic model which is a commonly used model for describing the voiced part of the speech signal. We show that it can be beneficial to extend the model to take inharmonicities or the non-stationarity of speech into account. Extending the model...

  3. Human Amygdala Tracks a Feature-Based Valence Signal Embedded within the Facial Expression of Surprise.

    Science.gov (United States)

    Kim, M Justin; Mattek, Alison M; Bennett, Randi H; Solomon, Kimberly M; Shin, Jin; Whalen, Paul J

    2017-09-27

    Human amygdala function has been traditionally associated with processing the affective valence (negative vs positive) of an emotionally charged event, especially those that signal fear or threat. However, this account of human amygdala function can be explained by alternative views, which posit that the amygdala might be tuned to either (1) general emotional arousal (activation vs deactivation) or (2) specific emotion categories (fear vs happy). Delineating the pure effects of valence independent of arousal or emotion category is a challenging task, given that these variables naturally covary under many circumstances. To circumvent this issue and test the sensitivity of the human amygdala to valence values specifically, we measured the dimension of valence within the single facial expression category of surprise. Given the inherent valence ambiguity of this category, we show that surprised expression exemplars are attributed valence and arousal values that are uniquely and naturally uncorrelated. We then present fMRI data from both sexes, showing that the amygdala tracks these consensus valence values. Finally, we provide evidence that these valence values are linked to specific visual features of the mouth region, isolating the signal by which the amygdala detects this valence information. SIGNIFICANCE STATEMENT There is an open question as to whether human amygdala function tracks the valence value of cues in the environment, as opposed to either a more general emotional arousal value or a more specific emotion category distinction. Here, we demonstrate the utility of surprised facial expressions because exemplars within this emotion category take on valence values spanning the dimension of bipolar valence (positive to negative) at a consistent level of emotional arousal. Functional neuroimaging data showed that amygdala responses tracked the valence of surprised facial expressions, unconfounded by arousal. Furthermore, a machine learning classifier identified

  4. CGRP in human models of primary headaches

    DEFF Research Database (Denmark)

    Ashina, Håkan; Schytz, Henrik Winther; Ashina, Messoud

    2018-01-01

    experiments are likely due to assay variation; therefore, proper validation and standardization of an assay is needed. To what extent CGRP is involved in tension-type headache and cluster headache is unknown. CONCLUSION: Human models of primary headaches have elucidated the role of CGRP in headache...... pathophysiology and sparked great interest in developing new treatment strategies using CGRP antagonists and antibodies. Future studies applying more refined human experimental models should identify biomarkers of CGRP-induced primary headache and reveal whether CGRP provocation experiments could be used......OBJECTIVE: To review the role of CGRP in human models of primary headaches and to discuss methodological aspects and future directions. DISCUSSION: Provocation experiments demonstrated a heterogeneous CGRP migraine response in migraine patients. Conflicting CGRP plasma results in the provocation...

  5. Stochastic model for detection of signals in noise

    OpenAIRE

    Klein, Stanley A.; Levi, Dennis M.

    2009-01-01

    Fifty years ago Birdsall, Tanner, and colleagues made rapid progress in developing signal detection theory into a powerful psychophysical tool. One of their major insights was the utility of adding external noise to the signals of interest. These methods have been enhanced in recent years by the addition of multipass and classification-image methods for opening up the black box. There remain a number of as yet unresolved issues. In particular, Birdsall developed a theorem that large amounts o...

  6. Resveratrol Downregulates Interleukin-6-Stimulated Sonic Hedgehog Signaling in Human Acute Myeloid Leukemia

    Science.gov (United States)

    Su, Yu-Chieh; Li, Szu-Chin; Wu, Yin-Chi; Wang, Li-Min; Chao, K. S. Clifford; Liao, Hui-Fen

    2013-01-01

    IL-6 and sonic hedgehog (Shh) signaling molecules are considered to maintain the growth of cancer stem cells (CSCs). Resveratrol, an important integrant in traditional Chinese medicine, possesses certain antitumor effects. However, the mechanisms on regulating acute myeloid leukemia (AML) are unclear. This study first used human subjects to demonstrate that the plasma levels of IL-6 and IL-1β in AML patients were higher and lower, respectively, than healthy donors. The expression of Shh preproproteins, and C- and N-terminal Shh peptides increased in bone marrow and peripheral blood mononuclear cells isolated from AML patients, and the plasma N-Shh secretion was greater. To further clarify the effect of IL-6 and resveratrol in Shh signaling, human AML HL-60 cells were tested. IL-6 upregulated Shh and Gli-1 expression and was accompanied by an increase of cell viability. Resveratrol significantly decreased CSC-related Shh expression, Gli-1 nuclear translocation, and cell viability in IL-6-treated HL-60 cells and had synergistic effect with Shh inhibitor cyclopamine on inhibiting cell growth. Conclusions. IL-6 stimulated the growth of AML cells through Shh signaling, and this effect might be blocked by resveratrol. Further investigations of Shh as a prognostic marker and resveratrol as a therapeutic drug target to CSCs in AML are surely warranted. PMID:23533494

  7. Persistent Amplification of DNA Damage Signal Involved in Replicative Senescence of Normal Human Diploid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Masatoshi Suzuki

    2012-01-01

    Full Text Available Foci of phosphorylated histone H2AX and ATM are the surrogate markers of DNA double strand breaks. We previously reported that the residual foci increased their size after irradiation, which amplifies DNA damage signals. Here, we addressed whether amplification of DNA damage signal is involved in replicative senescence of normal human diploid fibroblasts. Large phosphorylated H2AX foci (>1.5 μm diameter were specifically detected in presenescent cells. The frequency of cells with large foci was well correlated with that of cells positive for senescence-associated β-galactosidase staining. Hypoxic cell culture condition extended replicative life span of normal human fibroblast, and we found that the formation of large foci delayed in those cells. Our immuno-FISH analysis revealed that large foci partially localized at telomeres in senescent cells. Importantly, large foci of phosphorylated H2AX were always colocalized with phosphorylated ATM foci. Furthermore, Ser15-phosphorylated p53 showed colocalization with the large foci. Since the treatment of senescent cells with phosphoinositide 3-kinase inhibitor, wortmannin, suppressed p53 phosphorylation, it is suggested that amplification of DNA damage signaling sustains persistent activation of ATM-p53 pathway, which is essential for replicative senescence.

  8. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

    International Nuclear Information System (INIS)

    Brunetto de Farias, Caroline; Heinen, Tiago Elias; Pereira dos Santos, Rafael; Abujamra, Ana Lucia; Schwartsmann, Gilberto

    2012-01-01

    Highlights: ► BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. ► TrkB inhibition potentiated the antitumor effect of cetuximab. ► BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

  9. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Brunetto de Farias, Caroline [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Heinen, Tiago Elias; Pereira dos Santos, Rafael [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Abujamra, Ana Lucia [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Schwartsmann, Gilberto [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); and others

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. Black-Right-Pointing-Pointer TrkB inhibition potentiated the antitumor effect of cetuximab. Black-Right-Pointing-Pointer BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

  10. A novel human-machine interface based on recognition of multi-channel facial bioelectric signals

    International Nuclear Information System (INIS)

    Razazadeh, Iman Mohammad; Firoozabadi, S. Mohammad; Golpayegani, S.M.R.H.; Hu, H.

    2011-01-01

    Full text: This paper presents a novel human-machine interface for disabled people to interact with assistive systems for a better quality of life. It is based on multichannel forehead bioelectric signals acquired by placing three pairs of electrodes (physical channels) on the Fron-tails and Temporalis facial muscles. The acquired signals are passes through a parallel filter bank to explore three different sub-bands related to facial electromyogram, electrooculogram and electroencephalogram. The root mean features of the bioelectric signals analyzed within non-overlapping 256 ms windows were extracted. The subtractive fuzzy c-means clustering method (SFCM) was applied to segment the feature space and generate initial fuzzy based Takagi-Sugeno rules. Then, an adaptive neuro-fuzzy inference system is exploited to tune up the premises and consequence parameters of the extracted SFCMs. rules. The average classifier discriminating ratio for eight different facial gestures (smiling, frowning, pulling up left/right lips corner, eye movement to left/right/up/down is between 93.04% and 96.99% according to different combinations and fusions of logical features. Experimental results show that the proposed interface has a high degree of accuracy and robustness for discrimination of 8 fundamental facial gestures. Some potential and further capabilities of our approach in human-machine interfaces are also discussed. (author)

  11. From deep-sea volcanoes to human pathogens: a conserved quorum-sensing signal in Epsilonproteobacteria.

    Science.gov (United States)

    Pérez-Rodríguez, Ileana; Bolognini, Marie; Ricci, Jessica; Bini, Elisabetta; Vetriani, Costantino

    2015-05-01

    Chemosynthetic Epsilonproteobacteria from deep-sea hydrothermal vents colonize substrates exposed to steep thermal and redox gradients. In many bacteria, substrate attachment, biofilm formation, expression of virulence genes and host colonization are partly controlled via a cell density-dependent mechanism involving signal molecules, known as quorum sensing. Within the Epsilonproteobacteria, quorum sensing has been investigated only in human pathogens that use the luxS/autoinducer-2 (AI-2) mechanism to control the expression of some of these functions. In this study we showed that luxS is conserved in Epsilonproteobacteria and that pathogenic and mesophilic members of this class inherited this gene from a thermophilic ancestor. Furthermore, we provide evidence that the luxS gene is expressed--and a quorum-sensing signal is produced--during growth of Sulfurovum lithotrophicum and Caminibacter mediatlanticus, two Epsilonproteobacteria from deep-sea hydrothermal vents. Finally, we detected luxS transcripts in Epsilonproteobacteria-dominated biofilm communities collected from deep-sea hydrothermal vents. Taken together, our findings indicate that the epsiloproteobacterial lineage of the LuxS enzyme originated in high-temperature geothermal environments and that, in vent Epsilonproteobacteria, luxS expression is linked to the production of AI-2 signals, which are likely produced in situ at deep-sea vents. We conclude that the luxS gene is part of the ancestral epsilonproteobacterial genome and represents an evolutionary link that connects thermophiles to human pathogens.

  12. Human Inferences about Sequences: A Minimal Transition Probability Model.

    Directory of Open Access Journals (Sweden)

    Florent Meyniel

    2016-12-01

    Full Text Available The brain constantly infers the causes of the inputs it receives and uses these inferences to generate statistical expectations about future observations. Experimental evidence for these expectations and their violations include explicit reports, sequential effects on reaction times, and mismatch or surprise signals recorded in electrophysiology and functional MRI. Here, we explore the hypothesis that the brain acts as a near-optimal inference device that constantly attempts to infer the time-varying matrix of transition probabilities between the stimuli it receives, even when those stimuli are in fact fully unpredictable. This parsimonious Bayesian model, with a single free parameter, accounts for a broad range of findings on surprise signals, sequential effects and the perception of randomness. Notably, it explains the pervasive asymmetry between repetitions and alternations encountered in those studies. Our analysis suggests that a neural machinery for inferring transition probabilities lies at the core of human sequence knowledge.

  13. Study on non-linear bistable dynamics model based EEG signal discrimination analysis method.

    Science.gov (United States)

    Ying, Xiaoguo; Lin, Han; Hui, Guohua

    2015-01-01

    Electroencephalogram (EEG) is the recording of electrical activity along the scalp. EEG measures voltage fluctuations generating from ionic current flows within the neurons of the brain. EEG signal is looked as one of the most important factors that will be focused in the next 20 years. In this paper, EEG signal discrimination based on non-linear bistable dynamical model was proposed. EEG signals were processed by non-linear bistable dynamical model, and features of EEG signals were characterized by coherence index. Experimental results showed that the proposed method could properly extract the features of different EEG signals.

  14. Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load.

    Directory of Open Access Journals (Sweden)

    Thomas Krusenstjerna-Hafstrøm

    2011-05-01

    Full Text Available GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load.Eight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1 after an intravenous GH bolus 2 after an intravenous GH bolus plus an oral glucose load (OGTT, and 3 after intravenous saline plus OGTT. Muscle biopsies were taken at t = 0, 30, 60, and 120. Blood was sampled at frequent intervals for assessment of GH, insulin, glucose, and free fatty acids (FFA.GH increased AUC(glucose after an OGTT (p<0.05 without significant changes in serum insulin levels. GH induced phosphorylation of STAT5 independently of the OGTT. Conversely, the OGTT induced acute phosphorylation of the insulin signaling proteins Akt (ser(473 and thr(308, and AS160.The combination of OGTT and GH suppressed Akt activation, whereas the downstream expression of AS160 was amplified by GH. WE CONCLUDED THE FOLLOWING: 1 A physiological GH bolus activates STAT5 signaling pathways in skeletal muscle irrespective of ambient glucose and insulin levels 2 Insulin resistance induced by GH occurs without a distinct suppression of insulin signaling proteins 3 The accentuation of the glucose-stimulated activation of AS 160 by GH does however indicate a potential crosstalk between insulin and GH.ClinicalTrials.gov NCT00477997.

  15. Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83.

    Directory of Open Access Journals (Sweden)

    Anne Müller

    Full Text Available The murine G-protein coupled receptor 83 (mGPR83 is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR such as the ghrelin receptor (GHSR or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function. Here, we investigated particular amino acids at the eNDo of human GPR83 (hGPR83 by side-directed mutagenesis to identify determinants of the internal ligand. These studies were accompanied by structure homology modeling to combine functional insights with structural information. The capacity for hetero-oligomer formation of hGPR83 with diverse family A GPCRs such as the melanocortin-4 receptor (MC4R was also investigated, with a specific emphasis on the impact of the eNDo on oligomerization and basal signaling properties. Finally, we demonstrate that hGPR83 exhibits an unusual basal signaling for different effectors, which also supports signaling promiscuity. hGPR83 interacts with a variety of hypothalamic GPCRs such as the MC4R or GHSR. These interactions are not dependent on the ectodomain and most likely occur at interfaces constituted in the transmembrane regions. Moreover, several amino acids at the transition between the eNDo and transmembrane helix 1 were identified, where mutations lead also to biased basal signaling modulation.

  16. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells.

    Science.gov (United States)

    Fonseca, Sonya G; Ishigaki, Shinsuke; Oslowski, Christine M; Lu, Simin; Lipson, Kathryn L; Ghosh, Rajarshi; Hayashi, Emiko; Ishihara, Hisamitsu; Oka, Yoshitomo; Permutt, M Alan; Urano, Fumihiko

    2010-03-01

    Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.

  17. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T.Y.; Sadat, U. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom); Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Miller, S.R. [GlaxoSmithKline, Biostatistics and Data Sciences, Harlow (United Kingdom); Walsh, S.R.; Boyle, J.R.; Gaunt, M.E. [Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom)

    2009-07-15

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T{sub 1}-weighted (T{sub 1}w), T{sub 2}*-weighted (T{sub 2}*w) and quantitative T{sub 2}* (qT{sub 2}*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T{sub 1}w, T{sub 2}*w and qT{sub 2}* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T{sub 1}w, T{sub 2}*w and qT{sub 2}* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T{sub 1}w, T{sub 2}*w and qT{sub 2}*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T{sub 1}w, T{sub 2}*w and qT{sub 2}* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  18. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    International Nuclear Information System (INIS)

    Tang, T.Y.; Sadat, U.; Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H.; Miller, S.R.; Walsh, S.R.; Boyle, J.R.; Gaunt, M.E.

    2009-01-01

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T 1 -weighted (T 1 w), T 2 *-weighted (T 2 *w) and quantitative T 2 * (qT 2 *) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T 1 w, T 2 *w and qT 2 * MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T 1 w, T 2 *w and qT 2 * sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T 1 w, T 2 *w and qT 2 *, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T 1 w, T 2 *w and qT 2 * signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  19. Identification of walking human model using agent-based modelling

    Science.gov (United States)

    Shahabpoor, Erfan; Pavic, Aleksandar; Racic, Vitomir

    2018-03-01

    The interaction of walking people with large vibrating structures, such as footbridges and floors, in the vertical direction is an important yet challenging phenomenon to describe mathematically. Several different models have been proposed in the literature to simulate interaction of stationary people with vibrating structures. However, the research on moving (walking) human models, explicitly identified for vibration serviceability assessment of civil structures, is still sparse. In this study, the results of a comprehensive set of FRF-based modal tests were used, in which, over a hundred test subjects walked in different group sizes and walking patterns on a test structure. An agent-based model was used to simulate discrete traffic-structure interactions. The occupied structure modal parameters found in tests were used to identify the parameters of the walking individual's single-degree-of-freedom (SDOF) mass-spring-damper model using 'reverse engineering' methodology. The analysis of the results suggested that the normal distribution with the average of μ = 2.85Hz and standard deviation of σ = 0.34Hz can describe human SDOF model natural frequency. Similarly, the normal distribution with μ = 0.295 and σ = 0.047 can describe the human model damping ratio. Compared to the previous studies, the agent-based modelling methodology proposed in this paper offers significant flexibility in simulating multi-pedestrian walking traffics, external forces and simulating different mechanisms of human-structure and human-environment interaction at the same time.

  20. Generative models of the human connectome.

    Science.gov (United States)

    Betzel, Richard F; Avena-Koenigsberger, Andrea; Goñi, Joaquín; He, Ye; de Reus, Marcel A; Griffa, Alessandra; Vértes, Petra E; Mišic, Bratislav; Thiran, Jean-Philippe; Hagmann, Patric; van den Heuvel, Martijn; Zuo, Xi-Nian; Bullmore, Edward T; Sporns, Olaf

    2016-01-01

    The human connectome represents a network map of the brain's wiring diagram and the pattern into which its connections are organized is thought to play an important role in cognitive function. The generative rules that shape the topology of the human connectome remain incompletely understood. Earlier work in model organisms has suggested that wiring rules based on geometric relationships (distance) can account for many but likely not all topological features. Here we systematically explore a family of generative models of the human connectome that yield synthetic networks designed according to different wiring rules combining geometric and a broad range of topological factors. We find that a combination of geometric constraints with a homophilic attachment mechanism can create synthetic networks that closely match many topological characteristics of individual human connectomes, including features that were not included in the optimization of the generative model itself. We use these models to investigate a lifespan dataset and show that, with age, the model parameters undergo progressive changes, suggesting a rebalancing of the generative factors underlying the connectome across the lifespan. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

    Science.gov (United States)

    Shepard, H. Michael; Brdlik, Cathleen M.; Schreiber, Hans

    2008-01-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences. PMID:18982164

  2. Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology.

    Science.gov (United States)

    Liu, Li-Li; Xian, Hua; Cao, Jing-Chen; Zhang, Chong; Zhang, Yong-Hui; Chen, Miao-Miao; Qian, Yi; Jiang, Ming

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARγ acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγ protein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARγ signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.

  3. Identifying colon cancer risk modules with better classification performance based on human signaling network.

    Science.gov (United States)

    Qu, Xiaoli; Xie, Ruiqiang; Chen, Lina; Feng, Chenchen; Zhou, Yanyan; Li, Wan; Huang, Hao; Jia, Xu; Lv, Junjie; He, Yuehan; Du, Youwen; Li, Weiguo; Shi, Yuchen; He, Weiming

    2014-10-01

    Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer. Copyright © 2013. Published by Elsevier Inc.

  4. Tyrosine kinase signalling in breast cancer: Modulation of tyrosine kinase signalling in human breast cancer through altered expression of signalling intermediates

    International Nuclear Information System (INIS)

    Kairouz, Rania; Daly, Roger J

    2000-01-01

    The past decade has seen the definition of key signalling pathways downstream of receptor tyrosine kinases (RTKs) in terms of their components and the protein-protein interactions that facilitate signal transduction. Given the strong evidence that links signalling by certain families of RTKs to the progression of breast cancer, it is not surprising that the expression profile of key downstream signalling intermediates in this disease has also come under scrutiny, particularly because some exhibit transforming potential or amplify mitogenic signalling pathways when they are overexpressed. Reflecting the diverse cellular processes regulated by RTKs, it is now clear that altered expression of such signalling proteins in breast cancer may influence not only cellular proliferation (eg Grb2) but also the invasive properties of the cancer cells (eg EMS1/cortactin)

  5. Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling.

    Science.gov (United States)

    Bretón-Romero, Rosa; Feng, Bihua; Holbrook, Monika; Farb, Melissa G; Fetterman, Jessica L; Linder, Erika A; Berk, Brittany D; Masaki, Nobuyuki; Weisbrod, Robert M; Inagaki, Elica; Gokce, Noyan; Fuster, Jose J; Walsh, Kenneth; Hamburg, Naomi M

    2016-03-01

    Endothelial dysfunction is linked to insulin resistance, inflammatory activation, and increased cardiovascular risk in diabetes mellitus; however, the mechanisms remain incompletely understood. Recent studies have identified proinflammatory signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a regulator of metabolic dysfunction with potential relevance to vascular function. We sought to gain evidence that increased activation of Wnt5a-JNK signaling contributes to impaired endothelial function in patients with diabetes mellitus. We measured flow-mediated dilation of the brachial artery and characterized freshly isolated endothelial cells by protein expression, eNOS activation, and nitric oxide production in 85 subjects with type 2 diabetes mellitus (n=42) and age- and sex-matched nondiabetic controls (n=43) and in human aortic endothelial cells treated with Wnt5a. Endothelial cells from patients with diabetes mellitus displayed 1.3-fold higher Wnt5a levels (P=0.01) along with 1.4-fold higher JNK activation (P<0.01) without a difference in total JNK levels. Higher JNK activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Inhibition of Wnt5a and JNK signaling restored insulin and A23187-mediated eNOS activation and improved nitric oxide production in endothelial cells from patients with diabetes mellitus. In endothelial cells from nondiabetic controls, rWnt5a treatment inhibited eNOS activation replicating the diabetic endothelial phenotype. In human aortic endothelial cells, Wnt5a-induced impairment of eNOS activation and nitric oxide production was reversed by Wnt5a and JNK inhibition. Our findings demonstrate that noncanonical Wnt5a signaling and JNK activity contribute to vascular insulin resistance and endothelial dysfunction and may represent a novel therapeutic opportunity to protect the vasculature in patients with diabetes mellitus. © 2016 American Heart

  6. Modeling the exergy behavior of human body

    International Nuclear Information System (INIS)

    Keutenedjian Mady, Carlos Eduardo; Silva Ferreira, Maurício; Itizo Yanagihara, Jurandir; Hilário Nascimento Saldiva, Paulo; Oliveira Junior, Silvio de

    2012-01-01

    Exergy analysis is applied to assess the energy conversion processes that take place in the human body, aiming at developing indicators of health and performance based on the concepts of exergy destroyed rate and exergy efficiency. The thermal behavior of the human body is simulated by a model composed of 15 cylinders with elliptical cross section representing: head, neck, trunk, arms, forearms, hands, thighs, legs, and feet. For each, a combination of tissues is considered. The energy equation is solved for each cylinder, being possible to obtain transitory response from the body due to a variation in environmental conditions. With this model, it is possible to obtain heat and mass flow rates to the environment due to radiation, convection, evaporation and respiration. The exergy balances provide the exergy variation due to heat and mass exchange over the body, and the exergy variation over time for each compartments tissue and blood, the sum of which leads to the total variation of the body. Results indicate that exergy destroyed and exergy efficiency decrease over lifespan and the human body is more efficient and destroys less exergy in lower relative humidities and higher temperatures. -- Highlights: ► In this article it is indicated an overview of the human thermal model. ► It is performed the energy and exergy analysis of the human body. ► Exergy destruction and exergy efficiency decreases with lifespan. ► Exergy destruction and exergy efficiency are a function of environmental conditions.

  7. Evaluation of the autoregression time-series model for analysis of a noisy signal

    International Nuclear Information System (INIS)

    Allen, J.W.

    1977-01-01

    The autoregression (AR) time-series model of a continuous noisy signal was statistically evaluated to determine quantitatively the uncertainties of the model order, the model parameters, and the model's power spectral density (PSD). The result of such a statistical evaluation enables an experimenter to decide whether an AR model can adequately represent a continuous noisy signal and be consistent with the signal's frequency spectrum, and whether it can be used for on-line monitoring. Although evaluations of other types of signals have been reported in the literature, no direct reference has been found to AR model's uncertainties for continuous noisy signals; yet the evaluation is necessary to decide the usefulness of AR models of typical reactor signals (e.g., neutron detector output or thermocouple output) and the potential of AR models for on-line monitoring applications. AR and other time-series models for noisy data representation are being investigated by others since such models require fewer parameters than the traditional PSD model. For this study, the AR model was selected for its simplicity and conduciveness to uncertainty analysis, and controlled laboratory bench signals were used for continuous noisy data. (author)

  8. Generating Human-Like Velocity-Adapted Jumping Gait from sEMG Signals for Bionic Leg’s Control

    Directory of Open Access Journals (Sweden)

    Weiwei Yu

    2017-01-01

    Full Text Available In the case of dynamic motion such as jumping, an important fact in sEMG (surface Electromyogram signal based control on exoskeletons, myoelectric prostheses, and rehabilitation gait is that multichannel sEMG signals contain mass data and vary greatly with time, which makes it difficult to generate compliant gait. Inspired by the fact that muscle synergies leading to dimensionality reduction may simplify motor control and learning, this paper proposes a new approach to generate flexible gait based on muscle synergies extracted from sEMG signal. Two questions were discussed and solved, the first one concerning whether the same set of muscle synergies can explain the different phases of hopping movement with various velocities. The second one is about how to generate self-adapted gait with muscle synergies while alleviating model sensitivity to sEMG transient changes. From the experimental results, the proposed method shows good performance both in accuracy and in robustness for producing velocity-adapted vertical jumping gait. The method discussed in this paper provides a valuable reference for the sEMG-based control of bionic robot leg to generate human-like dynamic gait.

  9. Characterization of primary cilia and Hedgehog signaling during development of the human pancreas and in human pancreatic duct cancer cell lines

    DEFF Research Database (Denmark)

    Nielsen, Sonja K; Møllgård, Kjeld; Clement, Christian A

    2008-01-01

    Hedgehog (Hh) signaling controls pancreatic development and homeostasis; aberrant Hh signaling is associated with several pancreatic diseases. Here we investigated the link between Hh signaling and primary cilia in the human developing pancreatic ducts and in cultures of human pancreatic duct...... adenocarcinoma cell lines, PANC-1 and CFPAC-1. We show that the onset of Hh signaling from human embryogenesis to fetal development is associated with accumulation of Hh signaling components Smo and Gli2 in duct primary cilia and a reduction of Gli3 in the duct epithelium. Smo, Ptc, and Gli2 localized to primary...... cilia of PANC-1 and CFPAC-1 cells, which may maintain high levels of nonstimulated Hh pathway activity. These findings indicate that primary cilia are involved in pancreatic development and postnatal tissue homeostasis....

  10. Bayesian Modeling of a Human MMORPG Player

    Science.gov (United States)

    Synnaeve, Gabriel; Bessière, Pierre

    2011-03-01

    This paper describes an application of Bayesian programming to the control of an autonomous avatar in a multiplayer role-playing game (the example is based on World of Warcraft). We model a particular task, which consists of choosing what to do and to select which target in a situation where allies and foes are present. We explain the model in Bayesian programming and show how we could learn the conditional probabilities from data gathered during human-played sessions.

  11. Jack Human Modelling Tool: A Review

    Science.gov (United States)

    2010-01-01

    design and evaluation [8] and evolved into the Computerised Biomechanical Man Model (Combiman), shown in Figure 2. Combiman was developed at the...unrealistic arrangement of tetrahedra (Figure 7) to a highly realistic human model based on current anthropometric, anatomical and biomechanical data...has long legs and a short torso may find it difficult to adjust the seat and rudder pedals to achieve the required over the nose vision, reach to

  12. Modeling human intention formation for human reliability assessment

    International Nuclear Information System (INIS)

    Woods, D.D.; Roth, E.M.; Pople, H. Jr.

    1988-01-01

    This paper describes a dynamic simulation capability for modeling how people form intentions to act in nuclear power plant emergency situations. This modeling tool, Cognitive Environment Simulation or CES, was developed based on techniques from artificial intelligence. It simulates the cognitive processes that determine situation assessment and intention formation. It can be used to investigate analytically what situations and factors lead to intention failures, what actions follow from intention failures (e.g. errors of omission, errors of commission, common mode errors), the ability to recover from errors or additional machine failures, and the effects of changes in the NPP person machine system. One application of the CES modeling environment is to enhance the measurement of the human contribution to risk in probabilistic risk assessment studies. (author)

  13. Modelling dengue epidemic spreading with human mobility

    Science.gov (United States)

    Barmak, D. H.; Dorso, C. O.; Otero, M.

    2016-04-01

    We explored the effect of human mobility on the spatio-temporal dynamics of Dengue with a stochastic model that takes into account the epidemiological dynamics of the infected mosquitoes and humans, with different mobility patterns of the human population. We observed that human mobility strongly affects the spread of infection by increasing the final size and by changing the morphology of the epidemic outbreaks. When the spreading of the disease is driven only by mosquito dispersal (flight), a main central focus expands diffusively. On the contrary, when human mobility is taken into account, multiple foci appear throughout the evolution of the outbreaks. These secondary foci generated throughout the outbreaks could be of little importance according to their mass or size compared with the largest main focus. However, the coalescence of these foci with the main one generates an effect, through which the latter develops a size greater than the one obtained in the case driven only by mosquito dispersal. This increase in growth rate due to human mobility and the coalescence of the foci are particularly relevant in temperate cities such as the city of Buenos Aires, since they give more possibilities to the outbreak to grow before the arrival of the low-temperature season. The findings of this work indicate that human mobility could be the main driving force in the dynamics of vector epidemics.

  14. Decoding Individual Finger Movements from One Hand Using Human EEG Signals

    Science.gov (United States)

    Gonzalez, Jania; Ding, Lei

    2014-01-01

    Brain computer interface (BCI) is an assistive technology, which decodes neurophysiological signals generated by the human brain and translates them into control signals to control external devices, e.g., wheelchairs. One problem challenging noninvasive BCI technologies is the limited control dimensions from decoding movements of, mainly, large body parts, e.g., upper and lower limbs. It has been reported that complicated dexterous functions, i.e., finger movements, can be decoded in electrocorticography (ECoG) signals, while it remains unclear whether noninvasive electroencephalography (EEG) signals also have sufficient information to decode the same type of movements. Phenomena of broadband power increase and low-frequency-band power decrease were observed in EEG in the present study, when EEG power spectra were decomposed by a principal component analysis (PCA). These movement-related spectral structures and their changes caused by finger movements in EEG are consistent with observations in previous ECoG study, as well as the results from ECoG data in the present study. The average decoding accuracy of 77.11% over all subjects was obtained in classifying each pair of fingers from one hand using movement-related spectral changes as features to be decoded using a support vector machine (SVM) classifier. The average decoding accuracy in three epilepsy patients using ECoG data was 91.28% with the similarly obtained features and same classifier. Both decoding accuracies of EEG and ECoG are significantly higher than the empirical guessing level (51.26%) in all subjects (pEEG as in ECoG, and demonstrates the feasibility of discriminating finger movements from one hand using EEG. These findings are promising to facilitate the development of BCIs with rich control signals using noninvasive technologies. PMID:24416360

  15. Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile

    Directory of Open Access Journals (Sweden)

    Jessica Mühlhaus

    2014-11-01

    Full Text Available The thyroid hormone derivative 3-iodothyronamine (3-T1AM exerts metabolic effects in vivo that contradict known effects of thyroid hormones. 3-T1AM acts as a trace amine-associated receptor 1 (TAAR1 agonist and activates Gs signaling in vitro. Interestingly, 3-T1AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T1AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8. By RT-qPCR and locked-nucleic-acid (LNA in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of Gs and/or Gi/o signaling. Activation of G-proteins Gq/11 and G12/13 was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T1AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal Gi/o signaling activity, a so far unknown signaling pathway for TAARs.

  16. Modeling the Pulse Signal by Wave-Shape Function and Analyzing by Synchrosqueezing Transform.

    Science.gov (United States)

    Wu, Hau-Tieng; Wu, Han-Kuei; Wang, Chun-Li; Yang, Yueh-Lung; Wu, Wen-Hsiang; Tsai, Tung-Hu; Chang, Hen-Hong

    2016-01-01

    We apply the recently developed adaptive non-harmonic model based on the wave-shape function, as well as the time-frequency analysis tool called synchrosqueezing transform (SST) to model and analyze oscillatory physiological signals. To demonstrate how the model and algorithm work, we apply them to study the pulse wave signal. By extracting features called the spectral pulse signature, and based on functional regression, we characterize the hemodynamics from the radial pulse wave signals recorded by the sphygmomanometer. Analysis results suggest the potential of the proposed signal processing approach to extract health-related hemodynamics features.

  17. Modeling the Pulse Signal by Wave-Shape Function and Analyzing by Synchrosqueezing Transform.

    Directory of Open Access Journals (Sweden)

    Hau-Tieng Wu

    Full Text Available We apply the recently developed adaptive non-harmonic model based on the wave-shape function, as well as the time-frequency analysis tool called synchrosqueezing transform (SST to model and analyze oscillatory physiological signals. To demonstrate how the model and algorithm work, we apply them to study the pulse wave signal. By extracting features called the spectral pulse signature, and based on functional regression, we characterize the hemodynamics from the radial pulse wave signals recorded by the sphygmomanometer. Analysis results suggest the potential of the proposed signal processing approach to extract health-related hemodynamics features.

  18. Modeling evolution of crosstalk in noisy signal transduction networks

    Science.gov (United States)

    Tareen, Ammar; Wingreen, Ned S.; Mukhopadhyay, Ranjan

    2018-02-01

    Signal transduction networks can form highly interconnected systems within cells due to crosstalk between constituent pathways. To better understand the evolutionary design principles underlying such networks, we study the evolution of crosstalk for two parallel signaling pathways that arise via gene duplication. We use a sequence-based evolutionary algorithm and evolve the network based on two physically motivated fitness functions related to information transmission. We find that one fitness function leads to a high degree of crosstalk while the other leads to pathway specificity. Our results offer insights on the relationship between network architecture and information transmission for noisy biomolecular networks.

  19. Modeling and Simulating Virtual Anatomical Humans

    NARCIS (Netherlands)

    Madehkhaksar, Forough; Luo, Zhiping; Pronost, Nicolas; Egges, Arjan

    2014-01-01

    This chapter presents human musculoskeletal modeling and simulation as a challenging field that lies between biomechanics and computer animation. One of the main goals of computer animation research is to develop algorithms and systems that produce plausible motion. On the other hand, the main

  20. Dual small-molecule targeting of SMAD signaling stimulates human induced pluripotent stem cells toward neural lineages.

    Directory of Open Access Journals (Sweden)

    Methichit Wattanapanitch

    Full Text Available Incurable neurological disorders such as Parkinson's disease (PD, Huntington's disease (HD, and Alzheimer's disease (AD are very common and can be life-threatening because of their progressive disease symptoms with limited treatment options. To provide an alternative renewable cell source for cell-based transplantation and as study models for neurological diseases, we generated induced pluripotent stem cells (iPSCs from human dermal fibroblasts (HDFs and then differentiated them into neural progenitor cells (NPCs and mature neurons by dual SMAD signaling inhibitors. Reprogramming efficiency was improved by supplementing the histone deacethylase inhibitor, valproic acid (VPA, and inhibitor of p160-Rho associated coiled-coil kinase (ROCK, Y-27632, after retroviral transduction. We obtained a number of iPS colonies that shared similar characteristics with human embryonic stem cells in terms of their morphology, cell surface antigens, pluripotency-associated gene and protein expressions as well as their in vitro and in vivo differentiation potentials. After treatment with Noggin and SB431542, inhibitors of the SMAD signaling pathway, HDF-iPSCs demonstrated rapid and efficient differentiation into neural lineages. Six days after neural induction, neuroepithelial cells (NEPCs were observed in the adherent monolayer culture, which had the ability to differentiate further into NPCs and neurons, as characterized by their morphology and the expression of neuron-specific transcripts and proteins. We propose that our study may be applied to generate neurological disease patient-specific iPSCs allowing better understanding of disease pathogenesis and drug sensitivity assays.

  1. Gestational Diabetes Alters Offspring DNA Methylation Profiles in Human and Rat: Identification of Key Pathways Involved in Endocrine System Disorders, Insulin Signaling, Diabetes Signaling, and ILK Signaling.

    Science.gov (United States)

    Petropoulos, Sophie; Guillemin, Claire; Ergaz, Zivanit; Dimov, Sergiy; Suderman, Matthew; Weinstein-Fudim, Liza; Ornoy, Asher; Szyf, Moshe

    2015-06-01

    Gestational diabetes is associated with risk for metabolic disease later in life. Using a cross-species approach in rat and humans, we examined the hypothesis that gestational diabetes during pregnancy triggers changes in the methylome of the offspring that might be mediating these risks. We show in a gestation diabetes rat model, the Cohen diabetic rat, that gestational diabetes triggers wide alterations in DNA methylation in the placenta in both candidate diabetes genes and genome-wide promoters, thus providing evidence for a causal relationship between diabetes during pregnancy and DNA methylation alterations. There is a significant overlap between differentially methylated genes in the placenta and the liver of the rat offspring. Several genes differentially methylated in rat placenta exposed to maternal diabetes are also differentially methylated in the human placenta of offspring exposed to gestational diabetes in utero. DNA methylation changes inversely correlate with changes in expression. The changes in DNA methylation affect known functional gene pathways involved in endocrine function, metabolism, and insulin responses. These data provide support to the hypothesis that early-life exposures and their effects on metabolic disease are mediated by DNA methylation changes. This has important diagnostic and therapeutic implications.

  2. A central role for TOR signalling in a yeast model for juvenile CLN3 disease

    Directory of Open Access Journals (Sweden)

    Michael E. Bond

    2015-11-01

    Full Text Available Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs or Batten disease in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.

  3. Modeling the effects of Multi-path propagation and scintillation on GPS signals

    Science.gov (United States)

    Habash Krause, L.; Wilson, S. J.

    2014-12-01

    GPS signals traveling through the earth's ionosphere are affected by charged particles that often disrupt the signal and the information it carries due to "scintillation", which resembles an extra noise source on the signal. These signals are also affected by weather changes, tropospheric scattering, and absorption from objects due to multi-path propagation of the signal. These obstacles cause distortion within information and fading of the signal, which ultimately results in phase locking errors and noise in messages. In this work, we attempted to replicate the distortion that occurs in GPS signals using a signal processing simulation model. We wanted to be able to create and identify scintillated signals so we could better understand the environment that caused it to become scintillated. Then, under controlled conditions, we simulated the receiver's ability to suppress scintillation in a signal. We developed a code in MATLAB that was programmed to: 1. Create a carrier wave and then plant noise (four different frequencies) on the carrier wave, 2. Compute a Fourier transform on the four different frequencies to find the frequency content of a signal, 3. Use a filter and apply it to the Fourier transform of the four frequencies and then compute a Signal-to-noise ratio to evaluate the power (in Decibels) of the filtered signal, and 4.Plot each of these components into graphs. To test the code's validity, we used user input and data from an AM transmitter. We determined that the amplitude modulated signal or AM signal would be the best type of signal to test the accuracy of the MATLAB code due to its simplicity. This code is basic to give students the ability to change and use it to determine the environment and effects of noise on different AM signals and their carrier waves. Overall, we were able to manipulate a scenario of a noisy signal and interpret its behavior and change due to its noisy components: amplitude, frequency, and phase shift.

  4. Natural brain-information interfaces: Recommending information by relevance inferred from human brain signals

    Science.gov (United States)

    Eugster, Manuel J. A.; Ruotsalo, Tuukka; Spapé, Michiel M.; Barral, Oswald; Ravaja, Niklas; Jacucci, Giulio; Kaski, Samuel

    2016-01-01

    Finding relevant information from large document collections such as the World Wide Web is a common task in our daily lives. Estimation of a user’s interest or search intention is necessary to recommend and retrieve relevant information from these collections. We introduce a brain-information interface used for recommending information by relevance inferred directly from brain signals. In experiments, participants were asked to read Wikipedia documents about a selection of topics while their EEG was recorded. Based on the prediction of word relevance, the individual’s search intent was modeled and successfully used for retrieving new relevant documents from the whole English Wikipedia corpus. The results show that the users’ interests toward digital content can be modeled from the brain signals evoked by reading. The introduced brain-relevance paradigm enables the recommendation of information without any explicit user interaction and may be applied across diverse information-intensive applications. PMID:27929077

  5. Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors

    DEFF Research Database (Denmark)

    Jørgensen, Niklas R; Henriksen, Zanne; Sørensen, Ole

    2002-01-01

    that human osteoclasts expressed functional P2Y1 receptors, but, unexpectedly, desensitization of P2Y1 did not block calcium signaling to osteoclasts. We also found that osteoclasts expressed functional P2X7 receptors and showed that pharmacological inhibition of these receptors blocked calcium signaling...

  6. Optical models of the human eye.

    Science.gov (United States)

    Atchison, David A; Thibos, Larry N

    2016-03-01

    Optical models of the human eye have been used in visual science for purposes such as providing a framework for explaining optical phenomena in vision, for predicting how refraction and aberrations are affected by change in ocular biometry and as computational tools for exploring the limitations imposed on vision by the optical system of the eye. We address the issue of what is understood by optical model eyes, discussing the 'encyclopaedia' and 'toy train' approaches to modelling. An extensive list of purposes of models is provided. We discuss many of the theoretical types of optical models (also schematic eyes) of varying anatomical accuracy, including single, three and four refracting surface variants. We cover the models with lens structure in the form of nested shells and gradient index. Many optical eye models give accurate predictions only for small angles and small fields of view. If aberrations and image quality are important to consider, such 'paraxial' model eyes must be replaced by 'finite model' eyes incorporating features such as aspheric surfaces, tilts and decentrations, wavelength-dependent media and curved retinas. Many optical model eyes are population averages and must become adaptable to account for age, gender, ethnicity, refractive error and accommodation. They can also be customised for the individual when extensive ocular biometry and optical performance data are available. We consider which optical model should be used for a particular purpose, adhering to the principle that the best model is the simplest fit for the task. We provide a glimpse into the future of optical models of the human eye. This review is interwoven with historical developments, highlighting the important people who have contributed so richly to our understanding of visual optics. © 2016 The Authors. Clinical and Experimental Optometry © 2016 Optometry Australia.

  7. A knowledge representation meta-model for rule-based modelling of signalling networks

    Directory of Open Access Journals (Sweden)

    Adrien Basso-Blandin

    2016-03-01

    Full Text Available The study of cellular signalling pathways and their deregulation in disease states, such as cancer, is a large and extremely complex task. Indeed, these systems involve many parts and processes but are studied piecewise and their literatures and data are consequently fragmented, distributed and sometimes—at least apparently—inconsistent. This makes it extremely difficult to build significant explanatory models with the result that effects in these systems that are brought about by many interacting factors are poorly understood. The rule-based approach to modelling has shown some promise for the representation of the highly combinatorial systems typically found in signalling where many of the proteins are composed of multiple binding domains, capable of simultaneous interactions, and/or peptide motifs controlled by post-translational modifications. However, the rule-based approach requires highly detailed information about the precise conditions for each and every interaction which is rarely available from any one single source. Rather, these conditions must be painstakingly inferred and curated, by hand, from information contained in many papers—each of which contains only part of the story. In this paper, we introduce a graph-based meta-model, attuned to the representation of cellular signalling networks, which aims to ease this massive cognitive burden on the rule-based curation process. This meta-model is a generalization of that used by Kappa and BNGL which allows for the flexible representation of knowledge at various levels of granularity. In particular, it allows us to deal with information which has either too little, or too much, detail with respect to the strict rule-based meta-model. Our approach provides a basis for the gradual aggregation of fragmented biological knowledge extracted from the literature into an instance of the meta-model from which we can define an automated translation into executable Kappa programs.

  8. Human Walking Pattern Recognition Based on KPCA and SVM with Ground Reflex Pressure Signal

    Directory of Open Access Journals (Sweden)

    Zhaoqin Peng

    2013-01-01

    Full Text Available Algorithms based on the ground reflex pressure (GRF signal obtained from a pair of sensing shoes for human walking pattern recognition were investigated. The dimensionality reduction algorithms based on principal component analysis (PCA and kernel principal component analysis (KPCA for walking pattern data compression were studied in order to obtain higher recognition speed. Classifiers based on support vector machine (SVM, SVM-PCA, and SVM-KPCA were designed, and the classification performances of these three kinds of algorithms were compared using data collected from a person who was wearing the sensing shoes. Experimental results showed that the algorithm fusing SVM and KPCA had better recognition performance than the other two methods. Experimental outcomes also confirmed that the sensing shoes developed in this paper can be employed for automatically recognizing human walking pattern in unlimited environments which demonstrated the potential application in the control of exoskeleton robots.

  9. Modelling and simulation of signal transductions in an apoptosis ...

    Indian Academy of Sciences (India)

    Prakash

    Structural Analysis of Metabolic Networks: Elementary Flux. Mode, Analogy to Petri Nets, and Application to Mycoplasma pneumoniae; German Conference on Bioinformatics 2000 pp 115–120. Takai-Igarashi T and Mizoguchi R 2004 Cell signalling networks ontology; In Silico Biol. 4 81–87. Thompson C 1995 Apoptosis in ...

  10. Modeling the diffusion magnetic resonance imaging signal inside neurons

    International Nuclear Information System (INIS)

    Nguyen, D V; Li, J R; Grebenkov, D S; Le Bihan, D

    2014-01-01

    The Bloch-Torrey partial differential equation (PDE) describes the complex transverse water proton magnetization due to diffusion-encoding magnetic field gradient pulses. The integral of the solution of this PDE yields the diffusion magnetic resonance imaging (dMRI) signal. In a complex medium such as cerebral tissue, it is difficult to explicitly link the dMRI signal to biological parameters such as the cellular geometry or the cellular volume fraction. Studying the dMRI signal arising from a single neuron can provide insight into how the geometrical structure of neurons influences the measured signal. We formulate the Bloch-Torrey PDE inside a single neuron, under no water exchange condition with the extracellular space, and show how to reduce the 3D simulation in the full neuron to a 3D simulation around the soma and 1D simulations in the neurites. We show that this latter approach is computationally much faster than full 3D simulation and still gives accurate results over a wide range of diffusion times

  11. Phonetic perspectives on modelling information in the speech signal

    Indian Academy of Sciences (India)

    Centre for Music and Science, Faculty of Music, University of Cambridge,. Cambridge .... However, to develop systems that can han- .... 1.2a Phonemes are not clearly identifiable in movement or in the acoustic speech signal: As ..... while the speaker role-played the part of a mother at a child's athletics meeting where the.

  12. Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells.

    Science.gov (United States)

    Santini, Roberta; Vinci, Maria C; Pandolfi, Silvia; Penachioni, Junia Y; Montagnani, Valentina; Olivito, Biagio; Gattai, Riccardo; Pimpinelli, Nicola; Gerlini, Gianni; Borgognoni, Lorenzo; Stecca, Barbara

    2012-09-01

    The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self-renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDH(high)), which is endowed with higher self-renewal and tumorigenic abilities than the ALDH(low) population. A good correlation between the number of ALDH(high) cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self-renewal in vitro and a reduction in the number of ALDH(high) melanoma stem cells. Finally, we show that interference with the HH-GLI pathway through lentiviral-mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDH(high) melanoma stem cells. In conclusion, our data indicate an essential role of the HH-GLI1 signaling in controlling self-renewal and tumor initiation of melanoma CSC/TIC. Targeting HH-GLI1 is thus predicted to reduce the melanoma stem cell compartment. Copyright © 2012 AlphaMed Press.

  13. Identification of a putative nuclear export signal motif in human NANOG homeobox domain

    International Nuclear Information System (INIS)

    Park, Sung-Won; Do, Hyun-Jin; Huh, Sun-Hyung; Sung, Boreum; Uhm, Sang-Jun; Song, Hyuk; Kim, Nam-Hyung; Kim, Jae-Hwan

    2012-01-01

    Highlights: ► We found the putative nuclear export signal motif within human NANOG homeodomain. ► Leucine-rich residues are important for human NANOG homeodomain nuclear export. ► CRM1-specific inhibitor LMB blocked the potent human NANOG NES-mediated nuclear export. -- Abstract: NANOG is a homeobox-containing transcription factor that plays an important role in pluripotent stem cells and tumorigenic cells. To understand how nuclear localization of human NANOG is regulated, the NANOG sequence was examined and a leucine-rich nuclear export signal (NES) motif ( 125 MQELSNILNL 134 ) was found in the homeodomain (HD). To functionally validate the putative NES motif, deletion and site-directed mutants were fused to an EGFP expression vector and transfected into COS-7 cells, and the localization of the proteins was examined. While hNANOG HD exclusively localized to the nucleus, a mutant with both NLSs deleted and only the putative NES motif contained (hNANOG HD-ΔNLSs) was predominantly cytoplasmic, as observed by nucleo/cytoplasmic fractionation and Western blot analysis as well as confocal microscopy. Furthermore, site-directed mutagenesis of the putative NES motif in a partial hNANOG HD only containing either one of the two NLS motifs led to localization in the nucleus, suggesting that the NES motif may play a functional role in nuclear export. Furthermore, CRM1-specific nuclear export inhibitor LMB blocked the hNANOG potent NES-mediated export, suggesting that the leucine-rich motif may function in CRM1-mediated nuclear export of hNANOG. Collectively, a NES motif is present in the hNANOG HD and may be functionally involved in CRM1-mediated nuclear export pathway.

  14. Model-based design of self-Adapting networked signal processing systems

    NARCIS (Netherlands)

    Oliveira Filho, J.A. de; Papp, Z.; Djapic, R.; Oostveen, J.C.

    2013-01-01

    The paper describes a model based approach for architecture design of runtime reconfigurable, large-scale, networked signal processing applications. A graph based modeling formalism is introduced to describe all relevant aspects of the design (functional, concurrency, hardware, communication,

  15. Sensory augmentation: integration of an auditory compass signal into human perception of space

    Science.gov (United States)

    Schumann, Frank; O’Regan, J. Kevin

    2017-01-01

    Bio-mimetic approaches to restoring sensory function show great promise in that they rapidly produce perceptual experience, but have the disadvantage of being invasive. In contrast, sensory substitution approaches are non-invasive, but may lead to cognitive rather than perceptual experience. Here we introduce a new non-invasive approach that leads to fast and truly perceptual experience like bio-mimetic techniques. Instead of building on existing circuits at the neural level as done in bio-mimetics, we piggy-back on sensorimotor contingencies at the stimulus level. We convey head orientation to geomagnetic North, a reliable spatial relation not normally sensed by humans, by mimicking sensorimotor contingencies of distal sounds via head-related transfer functions. We demonstrate rapid and long-lasting integration into the perception of self-rotation. Short training with amplified or reduced rotation gain in the magnetic signal can expand or compress the perceived extent of vestibular self-rotation, even with the magnetic signal absent in the test. We argue that it is the reliability of the magnetic signal that allows vestibular spatial recalibration, and the coding scheme mimicking sensorimotor contingencies of distal sounds that permits fast integration. Hence we propose that contingency-mimetic feedback has great potential for creating sensory augmentation devices that achieve fast and genuinely perceptual experiences. PMID:28195187

  16. A Feasibility Study on Detection of Insider Threats based on Human Bio-signals

    Energy Technology Data Exchange (ETDEWEB)

    Suh, Young A; Yim, Man-Sung [KAIST, Daejeon (Korea, Republic of)

    2016-10-15

    The insider threat means that trusted workers in an organization might carry out harmful acts from the negligent use of classified data to potentially sabotage the workplace. Surveys and studies conducted over the last decade have consistently shown the critical nature of the insider threats problem, in both government and private sectors. The shortcomings of existing systems, such as mental self-assessment and peer review, are very subjective, biased-assessments and employed infrequently. To overcome these limitations, this study investigates the feasibility of detecting and predicting an insider threat by using human biodata, from smart wearable devices. This paper showed the feasibility of predicting and detecting insider threats using EEG, GSR and ECG signals. In the section 2.1, two research hypotheses were established to identify the significant difference on EEG, GSR and ECG signals when the subject decided bad action and is the placed in deceit situation. These hypotheses were tested using two kinds of pilot experiments in the form of input (stimulus) and output (checking response of physiological signals and reaction time)

  17. Assessment of Homomorphic Analysis for Human Activity Recognition from Acceleration Signals.

    Science.gov (United States)

    Vanrell, Sebastian Rodrigo; Milone, Diego Humberto; Rufiner, Hugo Leonardo

    2017-07-03

    Unobtrusive activity monitoring can provide valuable information for medical and sports applications. In recent years, human activity recognition has moved to wearable sensors to deal with unconstrained scenarios. Accelerometers are the preferred sensors due to their simplicity and availability. Previous studies have examined several \\azul{classic} techniques for extracting features from acceleration signals, including time-domain, time-frequency, frequency-domain, and other heuristic features. Spectral and temporal features are the preferred ones and they are generally computed from acceleration components, leaving the acceleration magnitude potential unexplored. In this study, based on homomorphic analysis, a new type of feature extraction stage is proposed in order to exploit discriminative activity information present in acceleration signals. Homomorphic analysis can isolate the information about whole body dynamics and translate it into a compact representation, called cepstral coefficients. Experiments have explored several configurations of the proposed features, including size of representation, signals to be used, and fusion with other features. Cepstral features computed from acceleration magnitude obtained one of the highest recognition rates. In addition, a beneficial contribution was found when time-domain and moving pace information was included in the feature vector. Overall, the proposed system achieved a recognition rate of 91.21% on the publicly available SCUT-NAA dataset. To the best of our knowledge, this is the highest recognition rate on this dataset.

  18. Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies.

    Science.gov (United States)

    Bocharov, Eduard V; Lesovoy, Dmitry M; Goncharuk, Sergey A; Goncharuk, Marina V; Hristova, Kalina; Arseniev, Alexander S

    2013-11-05

    Fibroblast growth factor receptor 3 (FGFR3) transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease. Eight different pathogenic mutations, implicated in cancers and growth disorders, have been identified in the FGFR3 transmembrane segment. Here, we describe the dimerization of the FGFR3 transmembrane domain in membrane-mimicking DPC/SDS (9/1) micelles. In the solved NMR structure, the two transmembrane helices pack into a symmetric left-handed dimer, with intermolecular stacking interactions occurring in the dimer central region. Some pathogenic mutations fall within the helix-helix interface, whereas others are located within a putative alternative interface. This implies that although the observed dimer structure is important for FGFR3 signaling, the mechanism of FGFR3-mediated transduction across the membrane is complex. We propose an FGFR3 signaling mechanism that is based on the solved structure, available structures of isolated soluble FGFR domains, and published biochemical and biophysical data. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. A Simple Decision Rule for Recognition of Poly(A) Tail Signal Motifs in Human Genome

    KAUST Repository

    AbouEisha, Hassan M.

    2015-05-12

    Background is the numerous attempts were made to predict motifs in genomic sequences that correspond to poly (A) tail signals. Vast portion of this effort has been directed to a plethora of nonlinear classification methods. Even when such approaches yield good discriminant results, identifying dominant features of regulatory mechanisms nevertheless remains a challenge. In this work, we look at decision rules that may help identifying such features. Findings are we present a simple decision rule for classification of candidate poly (A) tail signal motifs in human genomic sequence obtained by evaluating features during the construction of gradient boosted trees. We found that values of a single feature based on the frequency of adenine in the genomic sequence surrounding candidate signal and the number of consecutive adenine molecules in a well-defined region immediately following the motif displays good discriminative potential in classification of poly (A) tail motifs for samples covered by the rule. Conclusions is the resulting simple rule can be used as an efficient filter in construction of more complex poly(A) tail motifs classification algorithms.

  20. Modeling human infertility with pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Di Chen

    2017-05-01

    Full Text Available Human fertility is dependent upon the correct establishment and differentiation of the germline. This is because no other cell type in the body is capable of passing a genome and epigenome from parent to child. Terminally differentiated germline cells in the adult testis and ovary are called gametes. However, the initial specification of germline cells occurs in the embryo around the time of gastrulation. Most of our knowledge regarding the cell and molecular events that govern human germline specification involves extrapolating scientific principles from model organisms, most notably the mouse. However, recent work using next generation sequencing, gene editing and differentiation of germline cells from pluripotent stem cells has revealed that the core molecular mechanisms that regulate human germline development are different from rodents. Here, we will discuss the major molecular pathways required for human germline differentiation and how pluripotent stem cells have revolutionized our ability to study the earliest steps in human embryonic lineage specification in order to understand human fertility.

  1. Omni-PolyA: a method and tool for accurate recognition of Poly(A) signals in human genomic DNA

    KAUST Repository

    Magana-Mora, Arturo

    2017-08-15

    BackgroundPolyadenylation is a critical stage of RNA processing during the formation of mature mRNA, and is present in most of the known eukaryote protein-coding transcripts and many long non-coding RNAs. The correct identification of poly(A) signals (PAS) not only helps to elucidate the 3′-end genomic boundaries of a transcribed DNA region and gene regulatory mechanisms but also gives insight into the multiple transcript isoforms resulting from alternative PAS. Although progress has been made in the in-silico prediction of genomic signals, the recognition of PAS in DNA genomic sequences remains a challenge.ResultsIn this study, we analyzed human genomic DNA sequences for the 12 most common PAS variants. Our analysis has identified a set of features that helps in the recognition of true PAS, which may be involved in the regulation of the polyadenylation process. The proposed features, in combination with a recognition model, resulted in a novel method and tool, Omni-PolyA. Omni-PolyA combines several machine learning techniques such as different classifiers in a tree-like decision structure and genetic algorithms for deriving a robust classification model. We performed a comparison between results obtained by state-of-the-art methods, deep neural networks, and Omni-PolyA. Results show that Omni-PolyA significantly reduced the average classification error rate by 35.37% in the prediction of the 12 considered PAS variants relative to the state-of-the-art results.ConclusionsThe results of our study demonstrate that Omni-PolyA is currently the most accurate model for the prediction of PAS in human and can serve as a useful complement to other PAS recognition methods. Omni-PolyA is publicly available as an online tool accessible at www.cbrc.kaust.edu.sa/omnipolya/.

  2. Development of a realistic human airway model.

    Science.gov (United States)

    Lizal, Frantisek; Elcner, Jakub; Hopke, Philip K; Jedelsky, Jan; Jicha, Miroslav

    2012-03-01

    Numerous models of human lungs with various levels of idealization have been reported in the literature; consequently, results acquired using these models are difficult to compare to in vivo measurements. We have developed a set of model components based on realistic geometries, which permits the analysis of the effects of subsequent model simplification. A realistic digital upper airway geometry except for the lack of an oral cavity has been created which proved suitable both for computational fluid dynamics (CFD) simulations and for the fabrication of physical models. Subsequently, an oral cavity was added to the tracheobronchial geometry. The airway geometry including the oral cavity was adjusted to enable fabrication of a semi-realistic model. Five physical models were created based on these three digital geometries. Two optically transparent models, one with and one without the oral cavity, were constructed for flow velocity measurements, two realistic segmented models, one with and one without the oral cavity, were constructed for particle deposition measurements, and a semi-realistic model with glass cylindrical airways was developed for optical measurements of flow velocity and in situ particle size measurements. One-dimensional phase doppler anemometry measurements were made and compared to the CFD calculations for this model and good agreement was obtained.

  3. Profiling calcium signals of in vitro polarized human effector CD4+ T cells.

    Science.gov (United States)

    Kircher, Sarah; Merino-Wong, Maylin; Niemeyer, Barbara A; Alansary, Dalia

    2018-06-01

    Differentiation of naïve CD4 + T cells into effector subtypes with distinct cytokine profiles and physiological roles is a tightly regulated process, the imbalance of which can lead to an inadequate immune response or autoimmune disease. The crucial role of Ca 2+ signals, mainly mediated by the store operated Ca 2+ entry (SOCE) in shaping the immune response is well described. However, it is unclear if human effector CD4 + T cell subsets show differential Ca 2+ signatures in response to different stimulation methods. Herein, we provide optimized in vitro culture conditions for polarization of human CD4 + effector T cells and characterize their SOCE following both pharmacological store depletion and direct T-cell receptor (TCR) activation. Moreover, we measured whole cell Ca 2+ release activated Ca 2+ currents (I CRAC ) and investigated whether the observed differences correlate to the expression of CRAC genes. Our results show that Ca 2+ profiles of helper CD4 + Th1, Th2 and Th17 are distinct and in part shaped by the intensity of stimulation. Regulatory T cells (Treg) are unique being the subtype with the most prominent SOCE response. Analysis of in vivo differentiated Treg unraveled the role of differential expression of ORAI2 in fine-tuning signals in Treg vs. conventional CD4 + T cells. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

  4. Quorum sensing communication between bacteria and human cells: signals, targets and functions

    Directory of Open Access Journals (Sweden)

    Angelika eHolm

    2014-06-01

    Full Text Available Both direct and long-range interactions between pathogenic Pseudomonas aeruginosa bacteria and their eukaryotic hosts are important in the outcome of infections. For cell-to-cell communication, these bacteria employ the quorum sensing (QS system to pass on information of the density of the bacterial population and collectively switch on virulence factor production, biofilm formation and resistance development. Thus, QS allows bacteria to behave as a community to perform tasks which would be impossible for individual cells, e.g. to overcome defense and immune systems and establish infections in higher organisms. This review highlights these aspects of QS and our own recent research on how P.aeruginosa communicates with human cells using the small QS signal molecules N-acyl homoserine lactones (AHL. We focus on how this conversation changes the behavior and function of neutrophils, macrophages and epithelial cells and on how the signaling machinery in human cells responsible for the recognition of AHL. Understanding the bacteria-host relationships at both cellular and molecular levels is essential for the identification of new targets and for the development of novel strategies to fight bacterial infections in the future.

  5. No Effect of TETRA Hand Portable Transmission Signals on Human Cognitive Function and Symptoms

    DEFF Research Database (Denmark)

    Riddervold, Ingunn Skogstad; Kjærgaard, Søren K.; Pedersen, Gert F.

    2010-01-01

    Current radio frequency radiation exposure guidelines rest on well-established thermal effects. However, recent research into analogue and digital transmission fields at levels covered by the exposure guidelines has indicated possible detrimental effects on human cognitive performance. To investi......Current radio frequency radiation exposure guidelines rest on well-established thermal effects. However, recent research into analogue and digital transmission fields at levels covered by the exposure guidelines has indicated possible detrimental effects on human cognitive performance....... To investigate this, we conducted a controlled climate chamber study of possible changes in cognitive performance in healthy volunteers exposed to transmission signals from TETRA hand portables (TETRA handsets). The trial deployed a balanced, randomized, double-blinded cross-over design. Performance on different...... paper-and-pencil, auditory and computer-based cognitive tasks was monitored in 53 male volunteers (mean age 36.41 years, SD 8.35) during 45-min exposure to a TETRA handset and sham control signals remotely controlled from a laboratory more than 100 km away. The main cognitive outcome was the Trail...

  6. Domain altering SNPs in the human proteome and their impact on signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yichuan Liu

    Full Text Available Single nucleotide polymorphisms (SNPs constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders.

  7. Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

    Directory of Open Access Journals (Sweden)

    Kenichiro Ishii

    2018-04-01

    Full Text Available Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.

  8. Dickkopf-1 induced apoptosis in human placental choriocarcinoma is independent of canonical Wnt signaling

    International Nuclear Information System (INIS)

    Peng Sha; Miao Chenglin; Li Jing; Fan Xiujun; Cao Yujing; Duan Enkui

    2006-01-01

    Placental choriocarcinoma, a reproductive system carcinoma in women, has about 0.81% occurrence frequency in China, which leads to over 90% lethality due to indistinct pathogenesis and the absence of efficient therapeutic treatment. In the present study, using immunostaining and reverse transcription PCR, we reported that Dickkopf-1 (Dkk-1) is prominently expressed in human cytotrophoblast (CTB) cell, but absent in the human placental choriocarcinoma cell line JAR and JEG3, implicating an unknown correlation between Dkk-1 and carcinogenesis of placental choriocarcinoma. Further, through exogenous introduction of Dkk-1, we found repressed proliferation in JAR and JEG3, induced apoptosis in JAR, and discovered significant tumor suppression effects of Dkk-1 in placental choriocarcinoma. Moreover we found that this function of Dkk-1 is achieved through c-Jun N-terminal kinase (JNK), whereas the canonical Wnt pathway may not have a great role. This discovery is not symphonic to previous functional understanding of Dkk-1, a canonical Wnt signaling antagonist. Together, our data indicate the possible correlation between Dkk-1 and human placental choriocarcinoma and suggest potential applications of Dkk-1 in treatment of human placental choriocarcinomas

  9. Modeling Individual Cyclic Variation in Human Behavior.

    Science.gov (United States)

    Pierson, Emma; Althoff, Tim; Leskovec, Jure

    2018-04-01

    Cycles are fundamental to human health and behavior. Examples include mood cycles, circadian rhythms, and the menstrual cycle. However, modeling cycles in time series data is challenging because in most cases the cycles are not labeled or directly observed and need to be inferred from multidimensional measurements taken over time. Here, we present Cyclic Hidden Markov Models (CyH-MMs) for detecting and modeling cycles in a collection of multidimensional heterogeneous time series data. In contrast to previous cycle modeling methods, CyHMMs deal with a number of challenges encountered in modeling real-world cycles: they can model multivariate data with both discrete and continuous dimensions; they explicitly model and are robust to missing data; and they can share information across individuals to accommodate variation both within and between individual time series. Experiments on synthetic and real-world health-tracking data demonstrate that CyHMMs infer cycle lengths more accurately than existing methods, with 58% lower error on simulated data and 63% lower error on real-world data compared to the best-performing baseline. CyHMMs can also perform functions which baselines cannot: they can model the progression of individual features/symptoms over the course of the cycle, identify the most variable features, and cluster individual time series into groups with distinct characteristics. Applying CyHMMs to two real-world health-tracking datasets-of human menstrual cycle symptoms and physical activity tracking data-yields important insights including which symptoms to expect at each point during the cycle. We also find that people fall into several groups with distinct cycle patterns, and that these groups differ along dimensions not provided to the model. For example, by modeling missing data in the menstrual cycles dataset, we are able to discover a medically relevant group of birth control users even though information on birth control is not given to the model.

  10. FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

    Science.gov (United States)

    Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

    2014-01-01

    Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

  11. Microscopic Control Delay Modeling at Signalized Arterials Using Bluetooth Technology

    OpenAIRE

    Rajasekhar, Lakshmi

    2011-01-01

    Real-time control delay estimation is an important performance measure for any intersection to improve the signal timing plans dynamically in real-time and hence improve the overall system performance. Control delay estimates helps to determine the level-of-service (LOS) characteristics of various approaches at an intersection and takes into account deceleration delay, stopped delay and acceleration delay. All kinds of traffic delay calculation especially control delay calculation has always ...

  12. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  13. Effects of TGF-β signaling blockade on human A549 lung adenocarcinoma cell lines.

    Science.gov (United States)

    Xu, Cheng-Cheng; Wu, Lei-Ming; Sun, Wei; Zhang, Ni; Chen, Wen-Shu; Fu, Xiang-Ning

    2011-01-01

    Transforming growth factor β (TGF-β) is overexpressed in a wide variety of cancer types including lung adenocarcinoma (LAC), and the TGF-β signaling pathway plays an important role in tumor development. To determine whether blockade of the TGF-β signaling pathway can inhibit the malignant biological behavior of LAC, RNA interference (RNAi) technology was used to silence the expression of TGF-β receptor, type II (TGFβRII) in the LAC cell line, A549, and its effects on cell proliferation, invasion and metastasis were examined. Three specific small interfering RNAs (siRNAs) designed for targeting human TGFβRII were transfected into A549 cells. The expression of TGFβRII was detected by Western blot analysis. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The invasion and metastasis of A549 cells were investigated using the wound healing and Matrigel invasion assays. The expression of PI3K, phosphorylated Smad2, Smad4, Akt, Erk1/2, P38 and MMPs was detected by Western blot analysis. The TGFβRII siRNA significantly reduced the expression of TGFβRII in A549 cells. The knockdown of TGFβRII in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis. In addition to the Smad-dependent pathway, independent pathways including the Erk MAPK, PI3K/Akt and p38 MAPK pathways, as well as the expression of MMPs and VEGF, were inhibited. In conclusion, TGF-β signaling is required for LAC progression. Therefore, the blockade of this signaling pathway by the down-regulation of TGFβRII using SiRNA may provide a potential gene therapy for LAC.

  14. A speed guidance strategy for multiple signalized intersections based on car-following model

    Science.gov (United States)

    Tang, Tie-Qiao; Yi, Zhi-Yan; Zhang, Jian; Wang, Tao; Leng, Jun-Qiang

    2018-04-01

    Signalized intersection has great roles in urban traffic system. The signal infrastructure and the driving behavior near the intersection are paramount factors that have significant impacts on traffic flow and energy consumption. In this paper, a speed guidance strategy is introduced into a car-following model to study the driving behavior and the fuel consumption in a single-lane road with multiple signalized intersections. The numerical results indicate that the proposed model can reduce the fuel consumption and the average stop times. The findings provide insightful guidance for the eco-driving strategies near the signalized intersections.

  15. Modeling Operations Costs for Human Exploration Architectures

    Science.gov (United States)

    Shishko, Robert

    2013-01-01

    Operations and support (O&S) costs for human spaceflight have not received the same attention in the cost estimating community as have development costs. This is unfortunate as O&S costs typically comprise a majority of life-cycle costs (LCC) in such programs as the International Space Station (ISS) and the now-cancelled Constellation Program. Recognizing this, the Constellation Program and NASA HQs supported the development of an O&S cost model specifically for human spaceflight. This model, known as the Exploration Architectures Operations Cost Model (ExAOCM), provided the operations cost estimates for a variety of alternative human missions to the moon, Mars, and Near-Earth Objects (NEOs) in architectural studies. ExAOCM is philosophically based on the DoD Architecture Framework (DoDAF) concepts of operational nodes, systems, operational functions, and milestones. This paper presents some of the historical background surrounding the development of the model, and discusses the underlying structure, its unusual user interface, and lastly, previous examples of its use in the aforementioned architectural studies.

  16. On the role of exchange of power and information signals in control and stability of the human-robot interaction

    Science.gov (United States)

    Kazerooni, H.

    1991-01-01

    A human's ability to perform physical tasks is limited, not only by his intelligence, but by his physical strength. If, in an appropriate environment, a machine's mechanical power is closely integrated with a human arm's mechanical power under the control of the human intellect, the resulting system will be superior to a loosely integrated combination of a human and a fully automated robot. Therefore, we must develop a fundamental solution to the problem of 'extending' human mechanical power. The work presented here defines 'extenders' as a class of robot manipulators worn by humans to increase human mechanical strength, while the wearer's intellect remains the central control system for manipulating the extender. The human, in physical contact with the extender, exchanges power and information signals with the extender. The aim is to determine the fundamental building blocks of an intelligent controller, a controller which allows interaction between humans and a broad class of computer-controlled machines via simultaneous exchange of both power and information signals. The prevalent trend in automation has been to physically separate the human from the machine so the human must always send information signals via an intermediary device (e.g., joystick, pushbutton, light switch). Extenders, however are perfect examples of self-powered machines that are built and controlled for the optimal exchange of power and information signals with humans. The human wearing the extender is in physical contact with the machine, so power transfer is unavoidable and information signals from the human help to control the machine. Commands are transferred to the extender via the contact forces and the EMG signals between the wearer and the extender. The extender augments human motor ability without accepting any explicit commands: it accepts the EMG signals and the contact force between the person's arm and the extender, and the extender 'translates' them into a desired position. In

  17. Human airway eosinophils exhibit preferential reduction in STAT signaling capacity and increased CISH expression.

    Science.gov (United States)

    Burnham, Mandy E; Koziol-White, Cynthia J; Esnault, Stephane; Bates, Mary E; Evans, Michael D; Bertics, Paul J; Denlinger, Loren C

    2013-09-15

    Allergic asthma, a chronic respiratory disorder marked by inflammation and recurrent airflow obstruction, is associated with elevated levels of IL-5 family cytokines and elevated numbers of eosinophils (EOS). IL-5 family cytokines elongate peripheral blood EOS (EOS(PB)) viability, recruit EOS(PB) to the airways, and, at higher concentrations, induce degranulation and reactive oxygen species generation. Although airway EOS (EOS(A)) remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOS(A) with IL-5 family cytokines no longer confers a survival advantage. Because the IL-5 family receptors have common signaling capacity, but are uncoupled from EOS(A) survival, whereas other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOS(A) possess a JAK/STAT-specific regulatory mechanism (because JAK/STAT signaling is critical to EOS survival). We found that IL-5 family-induced STAT3 and STAT5 phosphorylation is attenuated in EOS(A) relative to blood EOS from airway allergen-challenged donors. However, IL-5 family-induced ERK1/2 phosphorylation is not altered between EOS(A) and EOS from airway allergen-challenged donors. These observations suggest EOS(A) possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOS(PB), IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOS(A) express significantly more CISH and SOCS1 mRNA and CISH protein than EOS(PB) counterparts. In EOS(PB), long-term pretreatment with IL-5 family cytokines, to varying degrees, attenuates IL-5 family-induced STAT5 phosphorylation. These data support a model in which IL-5 family cytokines trigger a selective downregulation mechanism in EOS(A) for JAK/STAT pathways.

  18. Human Airway Eosinophils Exhibit Preferential Reduction in STAT Signaling Capacity and Increased CISH Expression1

    Science.gov (United States)

    Burnham, Mandy E.; Koziol-White, Cynthia J.; Esnault, Stephane; Bates, Mary E.; Evans, Michael D.; Bertics, Paul J.; Denlinger, Loren C.

    2013-01-01

    Allergic asthma, a chronic respiratory disorder marked by inflammation and recurrent airflow obstruction, is associated with elevated levels of Interleukin-5 (IL-5) family cytokines, and elevated numbers of eosinophils (EOS). IL-5 family cytokines elongate peripheral blood EOS (EOSPB) viability, recruit EOSPB to the airways, and at higher concentrations, induce degranulation and reactive oxygen species (ROS) generation. While, EOSA remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOSA with IL-5 family cytokines no longer confers a survival advantage. Since the IL-5 family receptors have common signaling capacity, but are uncoupled from EOSA survival while other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOSA possess a JAK/STAT specific regulatory mechanism (since JAK/STAT signaling is critical to EOS survival). We found that IL-5 family-induced STAT3 and STAT5 phosphorylation is attenuated in EOSA relative to blood EOS from airway allergen-challenged donors (EOSCPB). However, IL-5 family induced ERK1/2 phosphorylation is not altered between EOSA and EOSCPB. These observations suggest EOSA possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOSPB, IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOSA express significantly more CISH and SOCS1 mRNA and CISH protein than EOSPB counterparts. In EOSPB, long-term pretreatment with IL-5 family cytokines, to varying degrees, attenuates IL-5 family induced STAT5 phosphorylation. These data support a model wherein IL-5 family cytokines trigger a selective down-regulation mechanism in EOSA for JAK/STAT pathways. PMID:23956426

  19. Computer Modeling of Human Delta Opioid Receptor

    Directory of Open Access Journals (Sweden)

    Tatyana Dzimbova

    2013-04-01

    Full Text Available The development of selective agonists of δ-opioid receptor as well as the model of interaction of ligands with this receptor is the subjects of increased interest. In the absence of crystal structures of opioid receptors, 3D homology models with different templates have been reported in the literature. The problem is that these models are not available for widespread use. The aims of our study are: (1 to choose within recently published crystallographic structures templates for homology modeling of the human δ-opioid receptor (DOR; (2 to evaluate the models with different computational tools; and (3 to precise the most reliable model basing on correlation between docking data and in vitro bioassay results. The enkephalin analogues, as ligands used in this study, were previously synthesized by our group and their biological activity was evaluated. Several models of DOR were generated using different templates. All these models were evaluated by PROCHECK and MolProbity and relationship between docking data and in vitro results was determined. The best correlations received for the tested models of DOR were found between efficacy (erel of the compounds, calculated from in vitro experiments and Fitness scoring function from docking studies. New model of DOR was generated and evaluated by different approaches. This model has good GA341 value (0.99 from MODELLER, good values from PROCHECK (92.6% of most favored regions and MolProbity (99.5% of favored regions. Scoring function correlates (Pearson r = -0.7368, p-value = 0.0097 with erel of a series of enkephalin analogues, calculated from in vitro experiments. So, this investigation allows suggesting a reliable model of DOR. Newly generated model of DOR receptor could be used further for in silico experiments and it will give possibility for faster and more correct design of selective and effective ligands for δ-opioid receptor.

  20. Human physiologically based pharmacokinetic model for propofol

    Directory of Open Access Journals (Sweden)

    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  1. WWC3 downregulation correlates with poor prognosis and inhibition of Hippo signaling in human gastric cancer

    Directory of Open Access Journals (Sweden)

    Hou J

    2017-06-01

    Full Text Available Jiabin Hou, Jin Zhou The First Affiliated Hospital, Harbin Medical University, Harbin, People’s Republic of China Abstract: The aim of this study was to investigate the clinicopathological significance and biological roles of WWC3 in human gastric cancer (GC. Clinical significance of WWC3 in human GCs was examined by using immunohistochemistry (IHC. WWC3 was downregulated in 48 of 111 human GCs, and its downregulation was associated with advanced stage, positive nodal status, and higher relapse rate. Importantly, WWC3 downregulation correlated with poor survival. It was also found that WWC3 protein expression was downregulated in GC cell lines compared with normal cell line GES-1. On one hand, WWC3 overexpression inhibited the cell growth rate and invading ability in HGC-27 cell line. On the other hand, depleting WWC3 by small interfering RNA (siRNA promoted proliferation rate and invading ability in the SGC-7901 cell line. In addition, cell cycle analysis showed that WWC3 overexpression inhibited while its depletion accelerated cell cycle progression at the G1/S transition. Western blot (WB analysis demonstrated that WWC3 repressed cyclin D1 and cyclin E while upregulated p27 expression. Luciferase reporter assay showed that WWC3 activated Hippo signaling pathway by suppressing TEAD transcription activity, with downregulation of total and nuclear YAP and its target CTGF. WWC3 siRNA depletion exhibited the opposite effects. In conclusion, this study indicates that WWC3 serves as a tumor suppressor in GC by activating Hippo signaling. Keywords: WWC3, gastric cancer, cell cycle, Hippo, YAP

  2. Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

    Science.gov (United States)

    Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

    2012-08-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

  3. A receptor-based model for dopamine-induced fMRI signal

    Science.gov (United States)

    Mandeville, Joseph. B.; Sander, Christin Y. M.; Jenkins, Bruce G.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel M.; Rosen, Bruce R.; Normandin, Marc D.

    2013-01-01

    This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine’s effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations. PMID:23466936

  4. Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis.

    Science.gov (United States)

    Sandefur, Conner I; Boucher, Richard C; Elston, Timothy C

    2017-08-29

    Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.

  5. Human Plague Risk: Spatial-Temporal Models

    Science.gov (United States)

    Pinzon, Jorge E.

    2010-01-01

    This chpater reviews the use of spatial-temporal models in identifying potential risks of plague outbreaks into the human population. Using earth observations by satellites remote sensing there has been a systematic analysis and mapping of the close coupling between the vectors of the disease and climate variability. The overall result is that incidence of plague is correlated to positive El Nino/Southem Oscillation (ENSO).

  6. Modeling and Simulation of Bus Dispatching Policy for Timed Transfers on Signalized Networks

    Science.gov (United States)

    Cho, Hsun-Jung; Lin, Guey-Shii

    2007-12-01

    The major work of this study is to formulate the system cost functions and to integrate the bus dispatching policy with signal control. The integrated model mainly includes the flow dispersion model for links, signal control model for nodes, and dispatching control model for transfer terminals. All such models are inter-related for transfer operations in one-center transit network. The integrated model that combines dispatching policies with flexible signal control modes can be applied to assess the effectiveness of transfer operations. It is found that, if bus arrival information is reliable, an early dispatching decision made at the mean bus arrival times is preferable. The costs for coordinated operations with slack times are relatively low at the optimal common headway when applying adaptive route control. Based on such findings, a threshold function of bus headway for justifying an adaptive signal route control under various time values of auto drivers is developed.

  7. The ontogeny of insulin signaling in the preterm baboon model.

    Science.gov (United States)

    Blanco, Cynthia L; Liang, Hanyu; Joya-Galeana, Joaquin; DeFronzo, Ralph A; McCurnin, Donald; Musi, Nicolas

    2010-05-01

    Hyperglycemia, a prevalent condition in premature infants, is thought to be a consequence of incomplete suppression of endogenous glucose production and reduced insulin-stimulated glucose disposal in peripheral tissues. However, the molecular basis for these conditions remains unclear. To test the hypothesis that the insulin transduction pathway is underdeveloped with prematurity, fetal baboons were delivered, anesthetized, and euthanized at 125 d gestational age (GA), 140 d GA, or near term at 175 d GA. Vastus lateralis muscle and liver tissues were obtained, and protein content of insulin signaling molecules [insulin receptor (IR)-beta, IR substate-1, p85 subunit of phosphatidylinositol 3-kinase, Akt, and AS160] and glucose transporters (GLUT)-1 and GLUT4 was measured by Western blotting. Muscle from 125 d GA baboons had markedly reduced GLUT1 protein content (16% of 140 d GA and 9% of 175 d GA fetuses). GLUT4 and AS160 also were severely reduced in 125 d GA fetal muscle (43% of 175 d GA and 35% of 175 d GA, respectively). In contrast, the protein content of IR-beta, IR substate-1, and Akt was elevated by 1.7-, 5.2-, and 1.9-fold, respectively, in muscle from 125 d GA baboons when compared with 175 d GA fetuses. No differences were found in the content of insulin signaling proteins in liver. In conclusion, significant gestational differences exist in the protein content of several insulin signaling proteins in the muscle of fetal baboons. Reduced muscle content of key glucose transport-regulating proteins (GLUT1, GLUT4, AS160) could play a role in the pathogenesis of neonatal hyperglycemia and reduced insulin-stimulated glucose disposal.

  8. MODELING HUMAN RELIABILITY ANALYSIS USING MIDAS

    Energy Technology Data Exchange (ETDEWEB)

    Ronald L. Boring; Donald D. Dudenhoeffer; Bruce P. Hallbert; Brian F. Gore

    2006-05-01

    This paper summarizes an emerging collaboration between Idaho National Laboratory and NASA Ames Research Center regarding the utilization of high-fidelity MIDAS simulations for modeling control room crew performance at nuclear power plants. The key envisioned uses for MIDAS-based control room simulations are: (i) the estimation of human error with novel control room equipment and configurations, (ii) the investigative determination of risk significance in recreating past event scenarios involving control room operating crews, and (iii) the certification of novel staffing levels in control rooms. It is proposed that MIDAS serves as a key component for the effective modeling of risk in next generation control rooms.

  9. The role of NF-κB signaling in the maintenance of pluripotency of human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Osamu Takase

    Full Text Available NF-κB signaling plays an essential role in maintaining the undifferentiated state of embryonic stem (ES cells. However, opposing roles of NF-κB have been reported in mouse and human ES cells, and the role of NF-κB in human induced pluripotent stem (iPS cells has not yet been clarified. Here, we report the role of NF-κB signaling in maintaining the undifferentiated state of human iPS cells. Compared with differentiated cells, undifferentiated human iPS cells showed an augmentation of NF-κB activity. During differentiation induced by the removal of feeder cells and FGF2, we observed a reduction in NF-κB activity, the expression of the undifferentiation markers Oct3/4 and Nanog, and the up-regulation of the differentiated markers WT-1 and Pax-2. The specific knockdown of NF-κB signaling using p65 siRNA also reduced the expression of Oct3/4 and Nanog and up-regulated WT-1 and Pax-2 but did not change the ES-like colony formation. Our results show that the augmentation of NF-κB signaling maintains the undifferentiated state of human iPS and suggest the importance of this signaling pathway in maintenance of human iPS cells.

  10. New ICRP human respiratory tract model

    International Nuclear Information System (INIS)

    Bailey, M.R.

    1993-01-01

    The new ICRP dosimetric model for the human respiratory tract is based on the premise that the large differences in radiation sensitivity of respiratory tract tissues, and the wide range of doses they receive argue for calculating specific tissue doses rather than average lung doses. The model is also directly applicable to the worldwide population of both workers and the public. The requirement to describe intake, and deposition, clearance and dosimetry in each respiratory tract region, for a wide range of subjects at various levels of exercise necessarily means that the model is more complex than that of ICRP Publication 30. The widespread use of powerful personal computers, and the availability of user-friendly software to implement the model, however, will make it widely and readily accessible when the report is published. (Author)

  11. Biomedical Simulation Models of Human Auditory Processes

    Science.gov (United States)

    Bicak, Mehmet M. A.

    2012-01-01

    Detailed acoustic engineering models that explore noise propagation mechanisms associated with noise attenuation and transmission paths created when using hearing protectors such as earplugs and headsets in high noise environments. Biomedical finite element (FE) models are developed based on volume Computed Tomography scan data which provides explicit external ear, ear canal, middle ear ossicular bones and cochlea geometry. Results from these studies have enabled a greater understanding of hearing protector to flesh dynamics as well as prioritizing noise propagation mechanisms. Prioritization of noise mechanisms can form an essential framework for exploration of new design principles and methods in both earplug and earcup applications. These models are currently being used in development of a novel hearing protection evaluation system that can provide experimentally correlated psychoacoustic noise attenuation. Moreover, these FE models can be used to simulate the effects of blast related impulse noise on human auditory mechanisms and brain tissue.

  12. Optimization of experimental human leukemia models (review

    Directory of Open Access Journals (Sweden)

    D. D. Pankov

    2012-01-01

    Full Text Available Actual problem of assessing immunotherapy prospects including antigenpecific cell therapy using animal models was covered in this review.Describe the various groups of currently existing animal models and methods of their creating – from different immunodeficient mice to severalvariants of tumor cells engraftment in them. The review addresses the possibility of tumor stem cells studying using mouse models for the leukemia treatment with adoptive cell therapy including WT1. Also issues of human leukemia cells migration and proliferation in a mice withdifferent immunodeficiency degree are discussed. To assess the potential immunotherapy efficacy comparison of immunodeficient mouse model with clinical situation in oncology patients after chemotherapy is proposed.

  13. Wideband Small-Signal Input dq Admittance Modeling of Six-Pulse Diode Rectifiers

    DEFF Research Database (Denmark)

    Yue, Xiaolong; Wang, Xiongfei; Blaabjerg, Frede

    2018-01-01

    This paper studies the wideband small-signal input dq admittance of six-pulse diode rectifiers. Considering the frequency coupling introduced by ripple frequency harmonics of d-and q-channel switching function, the proposed model successfully predicts the small-signal input dq admittance of six......-pulse diode rectifiers in high frequency regions that existing models fail to explain. Simulation and experimental results verify the accuracy of the proposed model....

  14. Human Splicing Finder: an online bioinformatics tool to predict splicing signals.

    Science.gov (United States)

    Desmet, François-Olivier; Hamroun, Dalil; Lalande, Marine; Collod-Béroud, Gwenaëlle; Claustres, Mireille; Béroud, Christophe

    2009-05-01

    Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effects of mutations on splicing signals or to identify splicing motifs in any human sequence. It contains all available matrices for auxiliary sequence prediction as well as new ones for binding sites of the 9G8 and Tra2-beta Serine-Arginine proteins and the hnRNP A1 ribonucleoprotein. We also developed new Position Weight Matrices to assess the strength of 5' and 3' splice sites and branch points. We evaluated HSF efficiency using a set of 83 intronic and 35 exonic mutations known to result in splicing defects. We showed that the mutation effect was correctly predicted in almost all cases. HSF could thus represent a valuable resource for research, diagnostic and therapeutic (e.g. therapeutic exon skipping) purposes as well as for global studies, such as the GEN2PHEN European Project or the Human Variome Project.

  15. Deregulation of a STAT3-IL8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness

    Science.gov (United States)

    de la Iglesia, Núria; Konopka, Genevieve; Lim, Kah Leong; Nutt, Catherine L.; Bromberg, Jacqueline F.; Frank, David A.; Mischel, Paul S.; Louis, David N.; Bonni, Azad

    2009-01-01

    Inactivation of the tumor suppressor PTEN is recognized as a major event in the pathogenesis of the brain tumor glioblastoma. However, the mechanisms by which PTEN loss specifically impacts the malignant behavior of glioblastoma cells including their proliferation and propensity for invasiveness remain poorly understood. Genetic studies suggest that the transcription factor STAT3 harbors a PTEN-regulated tumor suppressive function in mouse astrocytes. Here, we report that STAT3 plays a critical tumor suppressive role in PTEN-deficient human glioblastoma cells. Endogenous STAT3 signaling is specifically inhibited in PTEN-deficient glioblastoma cells. Strikingly, reactivation of STAT3 in PTEN-deficient glioblastoma cells inhibits their proliferation, invasiveness, and ability to spread on myelin. We also identify the chemokine IL8 as a novel target gene of STAT3 in human glioblastoma cells. Activated STAT3 occupies the endogenous IL8 promoter and directly represses IL8 transcription. Consistent with these results, IL8 is upregulated in PTEN-deficient human glioblastoma tumors. Importantly, IL8 repression mediates STAT3-inhibition of glioblastoma cell proliferation, invasiveness, and spreading on myelin. Collectively, our findings uncover a novel link between STAT3 and IL8 whose deregulation plays a key role in the malignant behavior of PTEN-deficient glioblastoma cells. These studies suggest that STAT3 activation or IL8 inhibition may have potential in patient-tailored treatment of PTEN-deficient brain tumors. PMID:18524891

  16. Human embryonic stem cell lines model experimental human cytomegalovirus latency.

    Science.gov (United States)

    Penkert, Rhiannon R; Kalejta, Robert F

    2013-05-28

    Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

  17. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    International Nuclear Information System (INIS)

    Perkins, Timothy N.; Dentener, Mieke A.; Stassen, Frank R.; Rohde, Gernot G.; Mossman, Brooke T.; Wouters, Emiel F.M.; Reynaert, Niki L.

    2016-01-01

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  18. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Perkins, Timothy N.; Dentener, Mieke A. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Stassen, Frank R. [Department of Medical Microbiology, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Rohde, Gernot G. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Mossman, Brooke T. [Department of Pathology, University of Vermont College of Medicine, Burlington, VT (United States); Wouters, Emiel F.M. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Reynaert, Niki L., E-mail: n.reynaert@maastrichtuniversity.nl [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands)

    2016-06-15

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  19. Toward understanding social cues and signals in human?robot interaction: effects of robot gaze and proxemic behavior

    OpenAIRE

    Fiore, Stephen M.; Wiltshire, Travis J.; Lobato, Emilio J. C.; Jentsch, Florian G.; Huang, Wesley H.; Axelrod, Benjamin

    2013-01-01

    As robots are increasingly deployed in settings requiring social interaction, research is needed to examine the social signals perceived by humans when robots display certain social cues. In this paper, we report a study designed to examine how humans interpret social cues exhibited by robots. We first provide a brief overview of perspectives from social cognition in humans and how these processes are applicable to human–robot interaction (HRI). We then discuss the need to examine the relatio...

  20. A Mouse Model for Human Anal Cancer

    Science.gov (United States)

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including but not limited to their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors; whereas, none of the like treated non-transgenic mice showed tumors. Histopathological analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID:20947489

  1. Modeling off-frequency binaural masking for short- and long-duration signals.

    Science.gov (United States)

    Nitschmann, Marc; Yasin, Ifat; Henning, G Bruce; Verhey, Jesko L

    2017-08-01

    Experimental binaural masking-pattern data are presented together with model simulations for 12- and 600-ms signals. The masker was a diotic 11-Hz wide noise centered on 500 Hz. The tonal signal was presented either diotically or dichotically (180° interaural phase difference) with frequencies ranging from 400 to 600 Hz. The results and the modeling agree with previous data and hypotheses; simulations with a binaural model sensitive to monaural modulation cues show that the effect of duration on off-frequency binaural masking-level differences is mainly a result of modulation cues which are only available in the monaural detection of long signals.

  2. A Variance Distribution Model of Surface EMG Signals Based on Inverse Gamma Distribution.

    Science.gov (United States)

    Hayashi, Hideaki; Furui, Akira; Kurita, Yuichi; Tsuji, Toshio

    2017-11-01

    Objective: This paper describes the formulation of a surface electromyogram (EMG) model capable of representing the variance distribution of EMG signals. Methods: In the model, EMG signals are handled based on a Gaussian white noise process with a mean of zero for each variance value. EMG signal variance is taken as a random variable that follows inverse gamma distribution, allowing the representation of noise superimposed onto this variance. Variance distribution estimation based on marginal likelihood maximization is also outlined in this paper. The procedure can be approximated using rectified and smoothed EMG signals, thereby allowing the determination of distribution parameters in real time at low computational cost. Results: A simulation experiment was performed to evaluate the accuracy of distribution estimation using artificially generated EMG signals, with results demonstrating that the proposed model's accuracy is higher than that of maximum-likelihood-based estimation. Analysis of variance distribution using real EMG data also suggested a relationship between variance distribution and signal-dependent noise. Conclusion: The study reported here was conducted to examine the performance of a proposed surface EMG model capable of representing variance distribution and a related distribution parameter estimation method. Experiments using artificial and real EMG data demonstrated the validity of the model. Significance: Variance distribution estimated using the proposed model exhibits potential in the estimation of muscle force. Objective: This paper describes the formulation of a surface electromyogram (EMG) model capable of representing the variance distribution of EMG signals. Methods: In the model, EMG signals are handled based on a Gaussian white noise process with a mean of zero for each variance value. EMG signal variance is taken as a random variable that follows inverse gamma distribution, allowing the representation of noise superimposed onto this

  3. Novel calibration model maintenance strategy for solving the signal instability in quantitative liquid chromatography-mass spectrometry.

    Science.gov (United States)

    Du, Hai-Li; Chen, Zeng-Ping; Song, Mi; Chen, Yao; Yu, Ru-Qin

    2014-04-18

    In this contribution, a multiplicative effects model with a parameter accounting for the variations in overall sensitivity over time was proposed to reduce the effects of signal instability on quantitative results of LC-MS/MS. This method allows the use of calibration models constructed from large standard sets without having to repeat their measurement even though variations occur in sensitivity and baseline signal intensity. The performance of the proposed method was tested on two proof-of-concept model systems: the determination of the target peptide in two sets of peptide digests mixtures and the quantification of melamine and metronidazole in two sets of milk powder samples. Experimental results confirmed that multiplicative effects model could provide quite satisfactory concentration predictions for both systems with average relative predictive error values far lower than the corresponding values of various models investigated in this paper. Considering its capability in solving the problem of signal instability across samples and over time in LC-MS/MS assays and its implementation simplicity, it is expected that the multiplicative effects model can be developed and extended in many application areas such as the quantification of specific protein in cells and human plasma and other complex systems. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts

    Directory of Open Access Journals (Sweden)

    Wen-Hsiung Chan

    2008-05-01

    Full Text Available Caffeine consumption is a risk factor for osteoporosis, but the precise regulatory mechanisms are currently unknown. Here, we show that cell viability decreases in osteoblasts treated with caffeine in a dose-dependent manner. This cell death is attributed primarily to apoptosis and to a smaller extent, necrosis. Moreover, caffeine directly stimulates intracellular oxidative stress. Our data support caffeine-induced apoptosis in osteoblasts via a mitochondria-dependent pathway. The apoptotic biochemical changes were effectively prevented upon pretreatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the caffeine-induced apoptotic cascade. Additionally, p21-activated protein kinase 2 (PAK2 and c-Jun N-terminal kinase (JNK were activated in caffeine-treated osteoblasts. Experiments further found that PAK2 activity is required for caffeine-induced JNK activation and apoptosis. Importantly, our data also show that caffeine triggers cell death via inactivation of the survival signal, including the ERK- and Akt-mediated anti-apoptotic pathways. Finally, exposure of rats to dietary water containing 10~20 μM caffeine led to bone mineral density loss. These results demonstrate for the first time that caffeine triggers apoptosis in osteoblasts via activation of mitochondria-dependent cell death signaling and inactivation of the survival signal, and causes bone mineral density loss in vivo.

  5. GenToS: Use of Orthologous Gene Information to Prioritize Signals from Human GWAS.

    Directory of Open Access Journals (Sweden)

    Anselm S Hoppmann

    Full Text Available Genome-wide association studies (GWAS evaluate associations between genetic variants and a trait or disease of interest free of prior biological hypotheses. GWAS require stringent correction for multiple testing, with genome-wide significance typically defined as association p-value <5*10-8. This study presents a new tool that uses external information about genes to prioritize SNP associations (GenToS. For a given list of candidate genes, GenToS calculates an appropriate statistical significance threshold and then searches for trait-associated variants in summary statistics from human GWAS. It thereby allows for identifying trait-associated genetic variants that do not meet genome-wide significance. The program additionally tests for enrichment of significant candidate gene associations in the human GWAS data compared to the number expected by chance. As proof of principle, this report used external information from a comprehensive resource of genetically manipulated and systematically phenotyped mice. Based on selected murine phenotypes for which human GWAS data for corresponding traits were publicly available, several candidate gene input lists were derived. Using GenToS for the investigation of candidate genes underlying murine skeletal phenotypes in data from a large human discovery GWAS meta-analysis of bone mineral density resulted in the identification of significantly associated variants in 29 genes. Index variants in 28 of these loci were subsequently replicated in an independent GWAS replication step, highlighting that they are true positive associations. One signal, COL11A1, has not been discovered through GWAS so far and represents a novel human candidate gene for altered bone mineral density. The number of observed genes that contained significant SNP associations in human GWAS based on murine candidate gene input lists was much greater than the number expected by chance across several complex human traits (enrichment p-value as

  6. A Signal Detection Model of Compound Decision Tasks

    Science.gov (United States)

    2006-12-01

    strict isolation (for many examples of such models see Egan, 1975; Macmillan & Creelman , 1991). The result has been twofold: A rich corpus of decision...Macmillan & Creelman , 1991). It is important to point out that SDT models are primarily decision models. They specify the rules and procedures for how...Broadbent, 1958; Macmillan & Creelman , 1991; Nolte & Jaarsma, 1967; Swensson & Judy, 1981; Tanner & Norman, 1954). To better understand how these two

  7. Small- and large-signal modeling of InP HBTs in transferred-substrate technology

    DEFF Research Database (Denmark)

    Johansen, Tom Keinicke; Rudolph, Matthias; Jensen, Thomas

    2014-01-01

    In this paper, the small- and large-signal modeling of InP heterojunction bipolar transistors (HBTs) in transferred substrate (TS) technology is investigated. The small-signal equivalent circuit parameters for TS-HBTs in two-terminal and three-terminal configurations are determined by employing...

  8. Model of multicomponent micro-Doppler signal in environment MatLab

    Directory of Open Access Journals (Sweden)

    Kucheryavenko Alexander

    2017-01-01

    Full Text Available The article illustrates the problem of measuring the speed glider component targets in the presence of a turboprop effect of the reflected signal in a pulse-Doppler radar, proposed a model turboprop signal component and an algorithm for its suppression

  9. HER/ErbB Receptor Interactions and Signaling Patterns in Human Mammary Epithelial Cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yi; Opresko, Lee K.; Shankaran, Harish; Chrisler, William B.; Wiley, H. S.; Resat, Haluk

    2009-10-31

    Knowledge about signaling pathways is typically compiled based on data gathered using different cell lines. This approach implicitly assumes that cell line dependence is not important, which can be misleading because different cell lines do not always respond to a particular stimulus in the same way. The lack of coherent data collected from closely related cellular systems can be detrimental to the efforts to understand the regulation of biological processes. In this study, we report the development of a library of human mammary epithelial (HME) cell lines which express endogenous levels of the cell surface receptor EGFR/HER1, and different levels of HER2 and HER3. Using our clone library, we have quantified the interactions among the HER1-3 receptors and systematically investigated the existing hypotheses about their interaction patterns. Contrary to earlier suggestions, we find that lateral interactions with HER2 do not lead to strong transactivation between EGFR and HER3. Our study identified HER2 as the dominant dimerization partner for both EGFR and HER3, and revealed that EGFR and HER3 activations are only weakly linked in HME cells. We have also quantified the time-dependent activation patterns of the downstream effectors Erk and Akt. We found that HER3 signaling makes the strongest contribution to Akt activation and that, stimulation of either EGFR or HER3 pathways activate Erk at significant levels. Our study shows that cell libraries formed from closely related clones can be a powerful resource for pursuing the quantitative investigations that are necessary for developing a systems level understanding of cell signaling.

  10. Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.

    Science.gov (United States)

    Yamasaki, Satoshi; Maeda, Motoi; Ohshima, Koichi; Kikuchi, Masahiro; Otsuka, Teruhisa; Harada, Mine

    2004-10-01

    Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.

  11. Effect of the opioid methionine enkephalinamide on signal transduction in human T-lymphocytes

    DEFF Research Database (Denmark)

    Sørensen, A N; Claesson, Mogens Helweg

    1998-01-01

    T cell receptor (TCR/CD3) induced fluctuations in intracellular free ionizied calcium, [Ca2+]i, was analysed in the human T leukemia cell clone, Jurkat, cultured in the presence of the opioid methionine enkephalinamide (Met-Enk) in titrated concentrations (10[-7] to 10[-15] M) or saline (PBS....... Moreover, the levels of [Ca2+]i in this particular fraction were lower than control levels prior to ligation of the TCR/CD3 complex. The data support the idea that signal transduction in T cells can be influenced by endogenous opioid. The data therefore give credit to the evolving hypothesis...... of a functional relationship between the neuroendocrine system and the immune system....

  12. Novel Flexible Wearable Sensor Materials and Signal Processing for Vital Sign and Human Activity Monitoring.

    Science.gov (United States)

    Servati, Amir; Zou, Liang; Wang, Z Jane; Ko, Frank; Servati, Peyman

    2017-07-13

    Advances in flexible electronic materials and smart textile, along with broad availability of smart phones, cloud and wireless systems have empowered the wearable technologies for significant impact on future of digital and personalized healthcare as well as consumer electronics. However, challenges related to lack of accuracy, reliability, high power consumption, rigid or bulky form factor and difficulty in interpretation of data have limited their wide-scale application in these potential areas. As an important solution to these challenges, we present latest advances in novel flexible electronic materials and sensors that enable comfortable and conformable body interaction and potential for invisible integration within daily apparel. Advances in novel flexible materials and sensors are described for wearable monitoring of human vital signs including, body temperature, respiratory rate and heart rate, muscle movements and activity. We then present advances in signal processing focusing on motion and noise artifact removal, data mining and aspects of sensor fusion relevant to future clinical applications of wearable technology.

  13. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells.

    Science.gov (United States)

    Sturgeon, Christopher M; Ditadi, Andrea; Awong, Geneve; Kennedy, Marion; Keller, Gordon

    2014-06-01

    Efforts to derive hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) are complicated by the fact that embryonic hematopoiesis consists of two programs, primitive and definitive, that differ in developmental potential. As only definitive hematopoiesis generates HSCs, understanding how this program develops is essential for being able to produce this cell population in vitro. Here we show that both hematopoietic programs transition through hemogenic endothelial intermediates and develop from KDR(+)CD34(-)CD144(-) progenitors that are distinguished by CD235a expression. Generation of primitive progenitors (KDR(+)CD235a(+)) depends on stage-specific activin-nodal signaling and inhibition of the Wnt-β-catenin pathway, whereas specification of definitive progenitors (KDR(+)CD235a(-)) requires Wnt-β-catenin signaling during this same time frame. Together, these findings establish simple selective differentiation strategies for the generation of primitive or definitive hematopoietic progenitors by Wnt-β-catenin manipulation, and in doing so provide access to enriched populations for future studies on hPSC-derived hematopoietic development.

  14. Effect of saw palmetto extract on PI3K cell signaling transduction in human glioma.

    Science.gov (United States)

    Yang, Yang; Hui, Lv; Yuqin, Che; Jie, Li; Shuai, Hou; Tiezhu, Zhou; Wei, Wang

    2014-08-01

    Saw palmetto extract can induce the apoptosis of prostate cancer cells. The aim of the present study was to investigate the effect of saw palmetto extract on the phosphatidylinositol 3-kinase (PI3K)/Akt signaling transduction pathway in human glioma U87 and U251 cell lines. Suspensions of U87 and U251 cells in a logarithmic growth phase were seeded into six-well plates at a density of 10 4 cells/well. In the experimental group, 1 μl/ml saw palmetto extract was added, while the control group was cultured without a drug for 24 h. The expression levels of PI3K, B-cell lymphoma-extra large (Bcl-xL) and p53 were evaluated through western blot analysis. In the experimental group, the U87 and U251 cells exhibited a lower expression level of PI3K protein as compared with the control group (t=6.849; Psaw palmetto extract induces glioma cell growth arrest and apoptosis via decreasing PI3K/Akt signal transduction.

  15. Small Molecules Affect Human Dental Pulp Stem Cell Properties Via Multiple Signaling Pathways

    Science.gov (United States)

    Al-Habib, Mey; Yu, Zongdong

    2013-01-01

    One fundamental issue regarding stem cells for regenerative medicine is the maintenance of stem cell stemness. The purpose of the study was to test whether small molecules can enhance stem cell properties of mesenchymal stem cells (MSCs) derived from human dental pulp (hDPSCs), which have potential for multiple clinical applications. We identified the effects of small molecules (Pluripotin (SC1), 6-bromoindirubin-3-oxime and rapamycin) on the maintenance of hDPSC properties in vitro and the mechanisms involved in exerting the effects. Primary cultures of hDPSCs were exposed to optimal concentrations of these small molecules. Treated hDPSCs were analyzed for their proliferation, the expression levels of pluripotent and MSC markers, differentiation capacities, and intracellular signaling activations. We found that small molecule treatments decreased cell proliferation and increased the expression of STRO-1, NANOG, OCT4, and SOX2, while diminishing cell differentiation into odonto/osteogenic, adipogenic, and neurogenic lineages in vitro. These effects involved Ras-GAP-, ERK1/2-, and mTOR-signaling pathways, which may preserve the cell self-renewal capacity, while suppressing differentiation. We conclude that small molecules appear to enhance the immature state of hDPSCs in culture, which may be used as a strategy for adult stem cell maintenance and extend their capacity for regenerative applications. PMID:23573877

  16. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    International Nuclear Information System (INIS)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A.

    2015-01-01

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer

  17. Phosphoproteomic fingerprinting of epidermal growth factor signaling and anticancer drug action in human tumor cells.

    Science.gov (United States)

    Lim, Yoon-Pin; Diong, Lang-Shi; Qi, Robert; Druker, Brian J; Epstein, Richard J

    2003-12-01

    Many proteins regulating cancer cell growth are tyrosine phosphorylated. Using antiphosphotyrosine affinity chromatography, thiourea protein solubilization, two-dimensional PAGE, and mass spectrometry, we report here the characterization of the epidermal growth factor (EGF)-induced phosphoproteome in A431 human epidermoid carcinoma cells. Using this approach, more than 50 distinct tyrosine phosphoproteins are identifiable within five main clusters-cytoskeletal proteins, signaling enzymes, SH2-containing adaptors, chaperones, and focal adhesion proteins. Comparison of the phosphoproteomes induced in vitro by transforming growth factor-alpha and platelet-derived growth factor demonstrates the pathway- and cell-specific nature of the phosphoproteomes induced. Elimination of both basal and ligand-dependent phosphoproteins by cell exposure to the EGF receptor catalytic inhibitor gefitinib (Iressa, ZD1839) suggests either an autocrine growth loop or the presence of a second inhibited kinase in A431 cells. By identifying distinct patterns of phosphorylation involving novel signaling substrates, and by clarifying the mechanism of action of anticancer drugs, these findings illustrate the potential of immunoaffinity-based phosphoproteomics for guiding the discovery of new drug targets and the rational utilization of pathway-specific chemotherapies.

  18. Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes.

    Directory of Open Access Journals (Sweden)

    Wai-Hong Tham

    2015-12-01

    Full Text Available The most severe form of malaria in humans is caused by the protozoan parasite Plasmodium falciparum. The invasive form of malaria parasites is termed a merozoite and it employs an array of parasite proteins that bind to the host cell to mediate invasion. In Plasmodium falciparum, the erythrocyte binding-like (EBL and reticulocyte binding-like (Rh protein families are responsible for binding to specific erythrocyte receptors for invasion and mediating signalling events that initiate active entry of the malaria parasite. Here we have addressed the role of the cytoplasmic tails of these proteins in activating merozoite invasion after receptor engagement. We show that the cytoplasmic domains of these type 1 membrane proteins are phosphorylated in vitro. Depletion of PfCK2, a kinase implicated to phosphorylate these cytoplasmic tails, blocks P. falciparum invasion of red blood cells. We identify the crucial residues within the PfRh4 cytoplasmic domain that are required for successful parasite invasion. Live cell imaging of merozoites from these transgenic mutants show they attach but do not penetrate erythrocytes implying the PfRh4 cytoplasmic tail conveys signals important for the successful completion of the invasion process.

  19. Towards Investigating Global Warming Impact on Human Health Using Derivatives of Photoplethysmogram Signals.

    Science.gov (United States)

    Elgendi, Mohamed; Norton, Ian; Brearley, Matt; Fletcher, Richard R; Abbott, Derek; Lovell, Nigel H; Schuurmans, Dale

    2015-10-14

    Recent clinical studies show that the contour of the photoplethysmogram (PPG) wave contains valuable information for characterizing cardiovascular activity. However, analyzing the PPG wave contour is difficult; therefore, researchers have applied first or higher order derivatives to emphasize and conveniently quantify subtle changes in the filtered PPG contour. Our hypothesis is that analyzing the whole PPG recording rather than each PPG wave contour or on a beat-by-beat basis can detect heat-stressed subjects and that, consequently, we will be able to investigate the impact of global warming on human health. Here, we explore the most suitable derivative order for heat stress assessment based on the energy and entropy of the whole PPG recording. The results of our study indicate that the use Int. J. Environ. Res. Public Health 2015, 7 12777 of the entropy of the seventh derivative of the filtered PPG signal shows promising results in detecting heat stress using 20-second recordings, with an overall accuracy of 71.6%. Moreover, the combination of the entropy of the seventh derivative of the filtered PPG signal with the root mean square of successive differences, or RMSSD (a traditional heart rate variability index of heat stress), improved the detection of heat stress to 88.9% accuracy.

  20. Towards Investigating Global Warming Impact on Human Health Using Derivatives of Photoplethysmogram Signals

    Directory of Open Access Journals (Sweden)

    Mohamed Elgendi

    2015-10-01

    Full Text Available Recent clinical studies show that the contour of the photoplethysmogram (PPG wave contains valuable information for characterizing cardiovascular activity. However, analyzing the PPG wave contour is difficult; therefore, researchers have applied first or higher order derivatives to emphasize and conveniently quantify subtle changes in the filtered PPG contour. Our hypothesis is that analyzing the whole PPG recording rather than each PPG wave contour or on a beat-by-beat basis can detect heat-stressed subjects and that, consequently, we will be able to investigate the impact of global warming on human health. Here, we explore the most suitable derivative order for heat stress assessment based on the energy and entropy of the whole PPG recording. The results of our study indicate that the use of the entropy of the seventh derivative of the filtered PPG signal shows promising results in detecting heat stress using 20-second recordings, with an overall accuracy of 71.6%. Moreover, the combination of the entropy of the seventh derivative of the filtered PPG signal with the root mean square of successive differences, or RMSSD (a traditional heart rate variability index of heat stress, improved the detection of heat stress to 88.9% accuracy.

  1. Towards Investigating Global Warming Impact on Human Health Using Derivatives of Photoplethysmogram Signals

    Science.gov (United States)

    Elgendi, Mohamed; Norton, Ian; Brearley, Matt; Fletcher, Richard R.; Abbott, Derek; Lovell, Nigel H.; Schuurmans, Dale

    2015-01-01

    Recent clinical studies show that the contour of the photoplethysmogram (PPG) wave contains valuable information for characterizing cardiovascular activity. However, analyzing the PPG wave contour is difficult; therefore, researchers have applied first or higher order derivatives to emphasize and conveniently quantify subtle changes in the filtered PPG contour. Our hypothesis is that analyzing the whole PPG recording rather than each PPG wave contour or on a beat-by-beat basis can detect heat-stressed subjects and that, consequently, we will be able to investigate the impact of global warming on human health. Here, we explore the most suitable derivative order for heat stress assessment based on the energy and entropy of the whole PPG recording. The results of our study indicate that the use of the entropy of the seventh derivative of the filtered PPG signal shows promising results in detecting heat stress using 20-second recordings, with an overall accuracy of 71.6%. Moreover, the combination of the entropy of the seventh derivative of the filtered PPG signal with the root mean square of successive differences, or RMSSD (a traditional heart rate variability index of heat stress), improved the detection of heat stress to 88.9% accuracy. PMID:26473907

  2. Omentin-1 Stimulates Human Osteoblast Proliferation through PI3K/Akt Signal Pathway

    Directory of Open Access Journals (Sweden)

    Shan-Shan Wu

    2013-01-01

    Full Text Available It has been presumed that adipokines deriving from adipose tissue may play important roles in bone metabolism. Omentin-1, a novel adipokine, which is selectively expressed in visceral adipose tissue, has been reported to stimulate proliferation and inhibit differentiation of mouse osteoblast. However, little information refers to the effect of omentin-1 on human osteoblast (hOB proliferation. The current study examined the potential effects of omentin-1 on proliferation in hOB and the signal pathway involved. Omentin-1 promoted hOB proliferation in a dose-dependent manner as determined by [3H]thymidine incorporation. Western blot analysis revealed that omentin-1 induced activation of Akt (phosphatidylinositol-3 kinase downstream effector and such effect was impeded by transfection of hOB with Akt-siRNA. Furthermore, LY294002 (a selective PI3K inhibitor and HIMO (a selective Akt inhibitor abolished the omentin-1-induced hOB proliferation. These findings indicate that omentin-1 induces hOB proliferation via the PI3K/Akt signaling pathway and suggest that osteoblast is a direct target of omentin-1.

  3. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A., E-mail: lsamant@uab.edu [Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, WTI320D, 1824 6th Avenue South, Birmingham, AL 35233 (United States)

    2015-07-21

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  4. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals

    International Nuclear Information System (INIS)

    Tong-Starksen, S.E.; Luciw, P.A.; Peterlin, B.M.

    1987-01-01

    Human immunodeficiency virus (HIV), the causative agent of AIDS, infects and kills lymphoid cells bearing the CD4 antigen. In an infected cell, a number of cellular as well as HIV-encoded gene products determine the levels of viral gene expression and HIV replication. Efficient HIV replication occurs in activated T cells. Utilizing transient expression assays, the authors show that gene expression directed by the HIV long terminal repeat (LTR) increases in response to T-cell activation signals. The effects of T-cell activation and of the HIV-encoded trans-activator (TAT) are multiplicative. Analysis of mutations and deletions in the HIV LTR reveals that the region responding to T-cell activation signals is located at positions -105 to -80. These sequences are composed of two direct repeats, which are homologous to the core transcriptional enhancer elements in the simian virus 40 genome. The studies reveal that these elements function as the HIV enhancer. By acting directly on the HIV LTR, T-cell activation may play an important role in HIV gene expression and in the activation of latent HIV

  5. Ultrasensitive, passive and wearable sensors for monitoring human muscle motion and physiological signals.

    Science.gov (United States)

    Cai, Feng; Yi, Changrui; Liu, Shichang; Wang, Yan; Liu, Lacheng; Liu, Xiaoqing; Xu, Xuming; Wang, Li

    2016-03-15

    Flexible sensors have attracted more and more attention as a fundamental part of anthropomorphic robot research, medical diagnosis and physical health monitoring. Here, we constructed an ultrasensitive and passive flexible sensor with the advantages of low cost, lightness and wearability, electric safety and reliability. The fundamental mechanism of the sensor is based on triboelectric effect inducing electrostatic charges on the surfaces between two different materials. Just like a plate capacitor, current will be generated while the distance or size of the parallel capacitors changes caused by the small mechanical disturbance upon it and therefore the output current/voltage will be produced. Typically, the passive sensor unambiguously monitors muscle motions including hand motion from stretch-clench-stretch, mouth motion from open-bite-open, blink and respiration. Moreover, this sensor records the details of the consecutive phases in a cardiac cycle of the apex cardiogram, and identify the peaks including percussion wave, tidal wave and diastolic wave of the radial pulse wave. To record subtle human physiological signals including radial pulsilogram and apex cardiogram with excellent signal/noise ratio, stability and reproducibility, the sensor shows great potential in the applications of medical diagnosis and daily health monitoring. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Unified and Modular Modeling and Functional Verification Framework of Real-Time Image Signal Processors

    Directory of Open Access Journals (Sweden)

    Abhishek Jain

    2016-01-01

    Full Text Available In VLSI industry, image signal processing algorithms are developed and evaluated using software models before implementation of RTL and firmware. After the finalization of the algorithm, software models are used as a golden reference model for the image signal processor (ISP RTL and firmware development. In this paper, we are describing the unified and modular modeling framework of image signal processing algorithms used for different applications such as ISP algorithms development, reference for hardware (HW implementation, reference for firmware (FW implementation, and bit-true certification. The universal verification methodology- (UVM- based functional verification framework of image signal processors using software reference models is described. Further, IP-XACT based tools for automatic generation of functional verification environment files and model map files are described. The proposed framework is developed both with host interface and with core using virtual register interface (VRI approach. This modeling and functional verification framework is used in real-time image signal processing applications including cellphone, smart cameras, and image compression. The main motivation behind this work is to propose the best efficient, reusable, and automated framework for modeling and verification of image signal processor (ISP designs. The proposed framework shows better results and significant improvement is observed in product verification time, verification cost, and quality of the designs.

  7. KIR2DL4 differentially signals downstream functions in human NK cells through distinct structural modules.

    Science.gov (United States)

    Miah, S M Shahjahan; Hughes, Tracey L; Campbell, Kerry S

    2008-03-01

    KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IkappaB kinase beta (IKKbeta) and the phosphorylation and degradation of IkappaBalpha, which indicate activation of the classical NF-kappaB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-alpha, IFN-gamma, MIP1alpha, MIP1beta, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-gamma, IL-8, and MIP1alpha production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-kappaB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcepsilonRI-gamma association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-kappaB pathway and selectively stimulated the production of MIP1alpha, but not that of IFN-gamma or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcepsilonRI-gamma; and 2) through another receptor domain independent of the transmembrane arginine.

  8. Modeling human reliability analysis using MIDAS

    International Nuclear Information System (INIS)

    Boring, R. L.

    2006-01-01

    This paper documents current efforts to infuse human reliability analysis (HRA) into human performance simulation. The Idaho National Laboratory is teamed with NASA Ames Research Center to bridge the SPAR-H HRA method with NASA's Man-machine Integration Design and Analysis System (MIDAS) for use in simulating and modeling the human contribution to risk in nuclear power plant control room operations. It is anticipated that the union of MIDAS and SPAR-H will pave the path for cost-effective, timely, and valid simulated control room operators for studying current and next generation control room configurations. This paper highlights considerations for creating the dynamic HRA framework necessary for simulation, including event dependency and granularity. This paper also highlights how the SPAR-H performance shaping factors can be modeled in MIDAS across static, dynamic, and initiator conditions common to control room scenarios. This paper concludes with a discussion of the relationship of the workload factors currently in MIDAS and the performance shaping factors in SPAR-H. (authors)

  9. The Five Key Questions of Human Performance Modeling.

    Science.gov (United States)

    Wu, Changxu

    2018-01-01

    Via building computational (typically mathematical and computer simulation) models, human performance modeling (HPM) quantifies, predicts, and maximizes human performance, human-machine system productivity and safety. This paper describes and summarizes the five key questions of human performance modeling: 1) Why we build models of human performance; 2) What the expectations of a good human performance model are; 3) What the procedures and requirements in building and verifying a human performance model are; 4) How we integrate a human performance model with system design; and 5) What the possible future directions of human performance modeling research are. Recent and classic HPM findings are addressed in the five questions to provide new thinking in HPM's motivations, expectations, procedures, system integration and future directions.

  10. In vitro and in vivo effects of zinc on cytokine signalling in human T cells.

    Science.gov (United States)

    Varin, Audrey; Larbi, Anis; Dedoussis, George V; Kanoni, Stavroula; Jajte, Jolanta; Rink, Lothar; Monti, Daniela; Malavolta, Marco; Marcellini, Fiorella; Mocchegiani, Eugenio; Herbein, Georges; Fulop, Tamas

    2008-05-01

    Aging is associated with changes in the immune response which are collectively called immunosenescence. The changes mainly affect the adaptive immune response and especially the T cell-mediated cellular immune response. There are a few data indicating that the cytokine signalling in T cells is altered with aging. Zinc has been specifically shown to have potent immunomodulatory effects. The aim of the present work was to study the IL-2 and IL-6 cytokine signalling and activation induced cell death (AICD) in T cells of elderly subjects of various ages and from various European countries. These experiments were performed in the frame of European Community financed project called ZINCAGE "Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic and lifestyle implications for healthy ageing", assembling 17 laboratories from 8 countries through Europe. The study was carried out in a total of 312 French and a group of 201 (26 from Italy, 63 from France, 57 from Greece, 24 from Poland and 30 from Germany) healthy non-institutionalized men and women older than 60 years of age, with available dietary data. Human peripheral blood mononuclear cells (PBMC) were obtained from heparinized blood and were stimulated in vitro by IL-2 or IL-6 for various periods and the phosphorylation of STAT3 and STAT5 was measured by FACScan. The activation induced cell death (AICD) was measured after anti-CD3 and CD28 restimulation for 48h by using the Annexin:FITC Apoptosis Kit. We found that there is an IL-2 signalling defect with aging up to 90 years of age which cannot be modulated by zinc. In contrast at 90 years and over the zinc could reverse the negative signalling effect of IL-2. There is also a signalling defect for STAT3 and STAT5 activation in T cells under IL-6 stimulation with aging and the zinc supplementation could potentiate only the STAT5 activation in the age-group 90 years and over. Studying signalling in PBL from different countries we detected less

  11. Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia.

    Science.gov (United States)

    Bergman, P; Seyedoleslami Esfahani, S; Engström, Y

    2017-01-01

    Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer. © 2017 Elsevier Inc. All rights reserved.

  12. Paradoxical Regulation of Human FGF21 by Both Fasting and Feeding Signals: Is FGF21 a Nutritional Adaptation Factor?

    Science.gov (United States)

    Uebanso, Takashi; Taketani, Yutaka; Yamamoto, Hironori; Amo, Kikuko; Ominami, Hirokazu; Arai, Hidekazu; Takei, Yuichiro; Masuda, Masashi; Tanimura, Ayako; Harada, Nagakatsu; Yamanaka-Okumura, Hisami; Takeda, Eiji

    2011-01-01

    Fibroblast growth factor 21 (FGF21) has recently emerged as a metabolic hormone involved in regulating glucose and lipid metabolism in mouse, but the regulatory mechanisms and actions of FGF21 in humans remain unclear. Here we have investigated the regulatory mechanisms of the human FGF21 gene at the transcriptional level. A deletion study of the human FGF21 promoter (−1672 to +230 bp) revealed two fasting signals, including peroxisome proliferator-activated receptor α (PPARα) and glucagon signals, that independently induced human FGF21 gene transcription in mouse primary hepatocytes. In addition, two feeding signals, glucose and xylitol, also dose-dependently induced human FGF21 gene transcription and mRNA expression in both human HepG2 cells and mouse primary hepatocytes. FGF21 protein expression and secretion were also induced by high glucose stimulation. The human FGF21 promoter (−1672 to +230 bp) was found to have a carbohydrate-responsive element at −380 to −366 bp, which is distinct from the PPAR response element (PPRE). Knock-down of the carbohydrate response element binding protein by RNAi diminished glucose-induced human FGF21 transcription. Moreover, we found that a region from −555 to −443 bp of the human FGF21 promoter region exerts an important role in the activation of basic transcription. In conclusion, human FGF21 gene expression is paradoxically and independently regulated by both fasting and feeding signals. These regulatory mechanisms suggest that human FGF21 is increased with nutritional crisis, including starvation and overfeeding. PMID:21829679

  13. Modeling the response of small myelinated axons in a compound nerve to kilohertz frequency signals.

    Science.gov (United States)

    Pelot, N A; Behrend, C E; Grill, W M

    2017-08-01

    There is growing interest in electrical neuromodulation of peripheral nerves, particularly autonomic nerves, to treat various diseases. Electrical signals in the kilohertz frequency (KHF) range can produce different responses, including conduction block. For example, EnteroMedics' vBloc ® therapy for obesity delivers 5 kHz stimulation to block the abdominal vagus nerves, but the mechanisms of action are unclear. We developed a two-part computational model, coupling a 3D finite element model of a cuff electrode around the human abdominal vagus nerve with biophysically-realistic electrical circuit equivalent (cable) model axons (1, 2, and 5.7 µm in diameter). We developed an automated algorithm to classify conduction responses as subthreshold (transmission), KHF-evoked activity (excitation), or block. We quantified neural responses across kilohertz frequencies (5-20 kHz), amplitudes (1-8 mA), and electrode designs. We found heterogeneous conduction responses across the modeled nerve trunk, both for a given parameter set and across parameter sets, although most suprathreshold responses were excitation, rather than block. The firing patterns were irregular near transmission and block boundaries, but otherwise regular, and mean firing rates varied with electrode-fibre distance. Further, we identified excitation responses at amplitudes above block threshold, termed 're-excitation', arising from action potentials initiated at virtual cathodes. Excitation and block thresholds decreased with smaller electrode-fibre distances, larger fibre diameters, and lower kilohertz frequencies. A point source model predicted a larger fraction of blocked fibres and greater change of threshold with distance as compared to the realistic cuff and nerve model. Our findings of widespread asynchronous KHF-evoked activity suggest that conduction block in the abdominal vagus nerves is unlikely with current clinical parameters. Our results indicate that compound neural or downstream muscle

  14. Modeling the response of small myelinated axons in a compound nerve to kilohertz frequency signals

    Science.gov (United States)

    Pelot, N. A.; Behrend, C. E.; Grill, W. M.

    2017-08-01

    Objective. There is growing interest in electrical neuromodulation of peripheral nerves, particularly autonomic nerves, to treat various diseases. Electrical signals in the kilohertz frequency (KHF) range can produce different responses, including conduction block. For example, EnteroMedics’ vBloc® therapy for obesity delivers 5 kHz stimulation to block the abdominal vagus nerves, but the mechanisms of action are unclear. Approach. We developed a two-part computational model, coupling a 3D finite element model of a cuff electrode around the human abdominal vagus nerve with biophysically-realistic electrical circuit equivalent (cable) model axons (1, 2, and 5.7 µm in diameter). We developed an automated algorithm to classify conduction responses as subthreshold (transmission), KHF-evoked activity (excitation), or block. We quantified neural responses across kilohertz frequencies (5-20 kHz), amplitudes (1-8 mA), and electrode designs. Main results. We found heterogeneous conduction responses across the modeled nerve trunk, both for a given parameter set and across parameter sets, although most suprathreshold responses were excitation, rather than block. The firing patterns were irregular near transmission and block boundaries, but otherwise regular, and mean firing rates varied with electrode-fibre distance. Further, we identified excitation responses at amplitudes above block threshold, termed ‘re-excitation’, arising from action potentials initiated at virtual cathodes. Excitation and block thresholds decreased with smaller electrode-fibre distances, larger fibre diameters, and lower kilohertz frequencies. A point source model predicted a larger fraction of blocked fibres and greater change of threshold with distance as compared to the realistic cuff and nerve model. Significance. Our findings of widespread asynchronous KHF-evoked activity suggest that conduction block in the abdominal vagus nerves is unlikely with current clinical parameters. Our

  15. Research on Healthy Anomaly Detection Model Based on Deep Learning from Multiple Time-Series Physiological Signals

    Directory of Open Access Journals (Sweden)

    Kai Wang

    2016-01-01

    Full Text Available Health is vital to every human being. To further improve its already respectable medical technology, the medical community is transitioning towards a proactive approach which anticipates and mitigates risks before getting ill. This approach requires measuring the physiological signals of human and analyzes these data at regular intervals. In this paper, we present a novel approach to apply deep learning in physiological signals analysis that allows doctor to identify latent risks. However, extracting high level information from physiological time-series data is a hard problem faced by the machine learning communities. Therefore, in this approach, we apply model based on convolutional neural network that can automatically learn features from raw physiological signals in an unsupervised manner and then based on the learned features use multivariate Gauss distribution anomaly detection method to detect anomaly data. Our experiment is shown to have a significant performance in physiological signals anomaly detection. So it is a promising tool for doctor to identify early signs of illness even if the criteria are unknown a priori.

  16. The quantitative modelling of human spatial habitability

    Science.gov (United States)

    Wise, J. A.

    1985-01-01

    A model for the quantitative assessment of human spatial habitability is presented in the space station context. The visual aspect assesses how interior spaces appear to the inhabitants. This aspect concerns criteria such as sensed spaciousness and the affective (emotional) connotations of settings' appearances. The kinesthetic aspect evaluates the available space in terms of its suitability to accommodate human movement patterns, as well as the postural and anthrometric changes due to microgravity. Finally, social logic concerns how the volume and geometry of available space either affirms or contravenes established social and organizational expectations for spatial arrangements. Here, the criteria include privacy, status, social power, and proxemics (the uses of space as a medium of social communication).

  17. A Novel Parametric Model For The Human Respiratory System

    Directory of Open Access Journals (Sweden)

    Clara Mihaela IONESCU

    2003-12-01

    Full Text Available The purpose of this work is to present some recent results in an ongoing research project between Ghent University and Chess Medical Technology Company Belgium. The overall aim of the project is to provide a fast method for identification of the human respiratory system in order to allow for an instantaneously diagnosis of the patient by the medical staff. A novel parametric model of the human respiratory system as well as the obtained experimental results is presented in this paper. A prototype apparatus developed by the company, based on the forced oscillation technique is used to record experimental data from 4 patients in this paper. Signal processing is based on spectral analysis and is followed by the parametric identification of a non-linear mechanistic model. The parametric model is equivalent to the structure of a simple electrical RLC-circuit, containing a non-linear capacitor. These parameters have a useful and easy-to-interpret physical meaning for the medical staff members.

  18. The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Wen-Shih Huang

    Full Text Available The stromal cell-derived factor-1 (SDF-1/CXC receptor 4 (CXCR4 axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC progression. In addition, metastatic CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA and 5-Fluorouracil (5FU to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBβ, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK, and phosphatidylinositol 3-kinase (PI3K/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC's resistance to chemotherapy.

  19. Computational Analysis and Simulation of Empathic Behaviors: a Survey of Empathy Modeling with Behavioral Signal Processing Framework.

    Science.gov (United States)

    Xiao, Bo; Imel, Zac E; Georgiou, Panayiotis; Atkins, David C; Narayanan, Shrikanth S

    2016-05-01

    Empathy is an important psychological process that facilitates human communication and interaction. Enhancement of empathy has profound significance in a range of applications. In this paper, we review emerging directions of research on computational analysis of empathy expression and perception as well as empathic interactions, including their simulation. We summarize the work on empathic expression analysis by the targeted signal modalities (e.g., text, audio, and facial expressions). We categorize empathy simulation studies into theory-based emotion space modeling or application-driven user and context modeling. We summarize challenges in computational study of empathy including conceptual framing and understanding of empathy, data availability, appropriate use and validation of machine learning techniques, and behavior signal processing. Finally, we propose a unified view of empathy computation and offer a series of open problems for future research.

  20. Modelling discontinuous well log signal to identify lithological ...

    Indian Academy of Sciences (India)

    1Indian School of Mines (ISM), Dhanbad 826 004, India. ... new wavelet transform-based algorithm to model the abrupt discontinuous changes from well log data by taking care of ...... the 11th ACM International Conference on Multimedia,.

  1. Large-Signal Code TESLA: Improvements in the Implementation and in the Model

    National Research Council Canada - National Science Library

    Chernyavskiy, Igor A; Vlasov, Alexander N; Anderson, Jr., Thomas M; Cooke, Simon J; Levush, Baruch; Nguyen, Khanh T

    2006-01-01

    We describe the latest improvements made in the large-signal code TESLA, which include transformation of the code to a Fortran-90/95 version with dynamical memory allocation and extension of the model...

  2. The quantitative modelling of human spatial habitability

    Science.gov (United States)

    Wise, James A.

    1988-01-01

    A theoretical model for evaluating human spatial habitability (HuSH) in the proposed U.S. Space Station is developed. Optimizing the fitness of the space station environment for human occupancy will help reduce environmental stress due to long-term isolation and confinement in its small habitable volume. The development of tools that operationalize the behavioral bases of spatial volume for visual kinesthetic, and social logic considerations is suggested. This report further calls for systematic scientific investigations of how much real and how much perceived volume people need in order to function normally and with minimal stress in space-based settings. The theoretical model presented in this report can be applied to any size or shape interior, at any scale of consideration, for the Space Station as a whole to an individual enclosure or work station. Using as a point of departure the Isovist model developed by Dr. Michael Benedikt of the U. of Texas, the report suggests that spatial habitability can become as amenable to careful assessment as engineering and life support concerns.

  3. Modelling human eye under blast loading.

    Science.gov (United States)

    Esposito, L; Clemente, C; Bonora, N; Rossi, T

    2015-01-01

    Primary blast injury (PBI) is the general term that refers to injuries resulting from the mere interaction of a blast wave with the body. Although few instances of primary ocular blast injury, without a concomitant secondary blast injury from debris, are documented, some experimental studies demonstrate its occurrence. In order to investigate PBI to the eye, a finite element model of the human eye using simple constitutive models was developed. The material parameters were calibrated by a multi-objective optimisation performed on available eye impact test data. The behaviour of the human eye and the dynamics of mechanisms occurring under PBI loading conditions were modelled. For the generation of the blast waves, different combinations of explosive (trinitrotoluene) mass charge and distance from the eye were analysed. An interpretation of the resulting pressure, based on the propagation and reflection of the waves inside the eye bulb and orbit, is proposed. The peculiar geometry of the bony orbit (similar to a frustum cone) can induce a resonance cavity effect and generate a pressure standing wave potentially hurtful for eye tissues.

  4. Rhein inhibits malignant phenotypes of human renal cell carcinoma by impacting on MAPK/NF-κB signaling pathways

    Directory of Open Access Journals (Sweden)

    Ma YL

    2018-03-01

    Full Text Available Ya-Li Ma,* Fang Chen,* Jun ShiDepartment of Nephrology, Huaihe Hospital Henan University, Kaifeng, People’s Republic of China*These authors contributed equally to this workBackground: Rhein, an anthraquinone derivative of rhubarb, is traditionally used in Chinese herbal medicine. Now emerging studies suggest its antitumor properties in many human cancers. The present study aims to investigate the antitumor role of Rhein and its possible mechanism in human renal cell carcinoma (RCC.Materials and methods: Three RCC cell lines (A489, 786-O and ACHN were used as the cell models. We applied CCK-8, cell counting, colony formation, wound healing and Transwell assays to assess the antitumor roles of Rhein in RCC cells in vitro. The therapeutic efficacy of Rhein was further evaluated by intraperitoneal administrations in tumor formation of mice. Western blot was used to investigate the underlying mechanisms of action of Rhein.Results: Rhein inhibited RCC cell proliferation in a dose- and time-dependent manner. It also suppressed RCC cell migration and invasion in vitro. Moreover, Rhein was able to inhibit tumor growth in nude mice by intraperitoneal administration in vivo. Mechanistically, the protein levels of phosphorylated MAPK (mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase, phosphorylated Akt and two targets of NF-κB (nuclear factor kappa-light-chain enhancer of activated B cells pathway, matrix metalloproteinase 9 and CCND1 were all markedly reduced by Rhein treatment.Conclusion: Rhein processed the antitumor effects in RCC cells by inhibiting cell proliferation, migration and invasion, and these tumor-suppressing functions might be mediated by MAPK/NF-κB signaling pathways.Keywords: Rhein, renal cell carcinoma, antitumor effects, MAPK, NF-κB

  5. Pulsatile blood flow in human bone assessed by laser-Doppler flowmetry and the interpretation of photoplethysmographic signals

    International Nuclear Information System (INIS)

    Binzoni, Tiziano; Tchernin, David; Hyacinthe, Jean-Noël; Van De Ville, Dimitri; Richiardi, Jonas

    2013-01-01

    Human bone blood flow, mean blood speed and the number of moving red blood cells were assessed (in arbitrary units), as a function