138 research outputs found

    Characterization of Spatiooral Cardiac Action Potential Variability at Baseline and under ß-Adrenergic Stimulation by Combined Unscented Kalman Filter and Double Greedy Dimension Reduction

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    Objective: Elevated spatiooral variability of human ventricular repolarization has been related to increased risk for ventricular arrhythmias and sudden cardiac death, particularly under ß-adrenergic stimulation (ß-AS). This work presents a methodology for theoretical characterization of temporal and spatial repolarization variability at baseline conditions and in response to ß-AS. For any measured voltage trace, the proposed methodology estimates the parameters and state variables of an underlying human ventricular action potential (AP) model by combining Double Greedy Dimension Reduction (DGDR) with automatic selection of biomarkers and the Unscented Kalman Filter (UKF). Such theoretical characterization can facilitate subsequent characterization of underlying variability mechanisms. Material and Methods: Given an AP trace, initial estimates for the ionic conductances in a stochastic version of the baseline human ventricular O'Hara et al. model were obtained by DGDR. Those estimates served to initialize and update model parameter estimates by the UKF method based on formulation of an associated nonlinear state-space representation and joint estimation of model parameters and state variables. Similarly, ß-AS-induced phosphorylation levels of cellular substrates were estimated by the DGDR-UKF methodology. Performance was tested by building an experimentally-calibrated population of virtual cells, from which synthetic AP traces were generated for baseline and ß-AS conditions. Results: The combined DGDR-UKF methodology led to 25% reduction in the error associated with estimation of ionic current conductances at baseline conditions and phosphorylation levels under ß-AS with respect to individual DGDR and UKF methods. This improvement was not at the expense of higher computational load, which was diminished by 90% with respect to the individual UKF method. Both temporal and spatial AP variability of repolarization were accurately characterized by the DGDR-UKF methodology. Conclusions: A combined DGDR-UKF methodology is proposed for parameter and state variable estimation of human ventricular cell models from available AP traces at baseline and under ß-AS. This methodology improves the estimation performance and reduces the convergence time with respect to individual DGDR and UKF methods and renders a suitable approach for computational characterization of spatiooral repolarization variability to be used for ascertainment of variability mechanisms and its relation to arrhythmogenesis

    Anti-inflammatory activity of Lychnophora passerina, Asteraceae (Brazilian “Arnica”)

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    AbstractEthnopharmacological relevanceLychnophora passerina (Asteraceae), popularly known as “arnica,” is used to treat inflammation, pain, rheumatism, contusions, bruises and insect bites in Brazilian traditional medicine.Materials and methodsThe anti-inflammatory activity of crude ethanolic extract of aerial parts of L. passerina and its ethyl acetate and methanolic fractions had their abilities to modulate the production of NO, TNF-α and IL-10 inflammatory mediators in LPS/IFN-Îł-stimulated J774.A1 macrophages evaluated. Moreover, the crude ethanolic extract and derived fractions were also in vivo assayed by carrageenan-induced paw oedema in mice.ResultsIn vitro assays showed remarkable anti-inflammatory activity of L. passerina crude ethanolic extract (EE) and its ethyl acetate (A) and methanolic (M) fractions, through the inhibition of production of NO and TNF-α inflammatory mediators and induction of production of IL-10 anti-inflammatory cytokine. In vivo assays showed anti-inflammatory activity for EE 10% ointment, similar to the standard drug diclofenac gel. The A and M fraction ointments 20% presented anti-inflammatory activity.ConclusionThe results obtained showed that possible anti-inflammatory effects of EE and its A and M fractions may be attributed to inhibition pro-inflammatory cytokines production, TNF-α and NO and to increased IL-10 production. EE, A and M ointments showed topical in vivo anti-inflammatory activity. The in vivo anti-inflammatory activity of EE of L. passerina may be related to synergistic effects of different substances in the crude extract. Therefore, traditional use of aerial parts of L. passerina in the inflammatory conditions could be beneficial to treat topical inflammatory conditions, as evidenced by the present study

    On the Testing of Seismicity Models

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    Recently a likelihood-based methodology has been developed by the Collaboratory for the Study of Earthquake Predictability (CSEP) with a view to testing and ranking seismicity models. We analyze this approach from the standpoint of possible applications to hazard analysis. We arrive at the conclusion that model testing can be made more efficient by focusing on some integral characteristics of the seismicity distribution. This is achieved either in the likelihood framework but with economical and physically reasonable coarsening of the phase space or by choosing a suitable measure of closeness between empirical and model seismicity rate in this space.Comment: To appear at Acta Geophysic

    An Oscillatory Contractile Pole-Force Component Dominates the Traction Forces Exerted by Migrating Amoeboid Cells

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    We used principal component analysis to dissect the mechanics of chemotaxis of amoeboid cells into a reduced set of dominant components of cellular traction forces and shape changes. The dominant traction force component in wild-type cells accounted for ~40% of the mechanical work performed by these cells, and consisted of the cell attaching at front and back contracting the substrate towards its centroid (pole-force). The time evolution of this pole-force component was responsible for the periodic variations of cell length and strain energy that the cells underwent during migration. We identified four additional canonical components, reproducible from cell to cell, overall accounting for an additional ~20% of mechanical work, and associated with events such as lateral protrusion of pseudopodia. We analyzed mutant strains with contractility defects to quantify the role that non-muscle Myosin II (MyoII) plays in amoeboid motility. In MyoII essential light chain null cells the polar-force component remained dominant. On the other hand, MyoII heavy chain null cells exhibited a different dominant traction force component, with a marked increase in lateral contractile forces, suggesting that cortical contractility and/or enhanced lateral adhesions are important for motility in this cell line. By compressing the mechanics of chemotaxing cells into a reduced set of temporally-resolved degrees of freedom, the present study may contribute to refined models of cell migration that incorporate cell-substrate interactions

    Severe asthma: One disease and multiple definitions

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    Introduction: There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods: Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results: 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions: The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem

    Detection of the blazar S4 0954+65 at very-high-energy with the MAGIC telescopes during an exceptionally high optical state

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    The very high energy (VHE Âż 100 GeV) -ray MAGIC observations of the blazar S4 0954+65, were triggered by an exceptionally high flux state of emission in the optical. This blazar has a disputed redshift of z = 0.368 or z Âż 0.45 and an uncertain classification among blazar subclasses. The exceptional source state described here makes for an excellent opportunity to understand physical processes in the jet of S4 0954+65 and thus contribute to its classification. Methods. We investigated the multiwavelength (MWL) light curve and spectral energy distribution (SED) of the S4 0954+65 blazar during an enhanced state in February 2015 and have put it in context with possible emission scenarios. We collected photometric data in radio, optical, X-ray, and Âż-ray. We studied both the optical polarization and the inner parsec-scale jet behavior with 43 GHz data. Results. Observations with the MAGIC telescopes led to the first detection of S4 0954+65 at VHE. Simultaneous data with Fermi-LAT at high energy Âż-ray(HE, 100 MeV < E < 100 GeV) also show a period of increased activity. Imaging at 43 GHz reveals the emergence of a new feature in the radio jet in coincidence with the VHE flare. Simultaneous monitoring of the optical polarization angle reveals a rotation of approximately 100. Conclusions. The high emission state during the flare allows us to compile the simultaneous broadband SED and to characterize it in the scope of blazar jet emission models. The broadband spectrum can be modeled with an emission mechanism commonly invoked for flat spectrum radio quasars (FSRQs), that is, inverse Compton scattering on an external soft photon field from the dust torus, also known as external Compton. The light curve and SED phenomenology is consistent with an interpretation of a blob propagating through a helical structured magnetic field and eventually crossing a standing shock in the jet, a scenario typically applied to FSRQs and low-frequency peaked BL Lac objects (LBL). © ESO 2018.The financial support of the German BMBF and MPG, the Italian INFN and INAF, the Swiss National Fund SNF, the ERDF under the Spanish MINECO (FPA2015-69818-P, FPA2012-36668, FPA2015-68378-P, FPA2015-69210-C6-2-R, FPA2015-69210-C6-4-R, FPA2015-69210-C6-6-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2015-71662-C2-2-P, CSD2009-00064), and the Japanese JSPS and MEXT is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia “Severo Ochoa” SEV-2012-0234 and SEV-2015-0548, and Unidad de Excelencia “MarĂ­a de Maeztu” MDM-2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ. IA acknowledges support by a RamĂłn y Cajal grant of the Ministerio de EconomĂ­a, Industria y Competitividad (MINECO) of Spain. The research at the IAA–CSIC was supported in part by the MINECO through grants AYA2016–80889–P, AYA2013–40825–P, and AYA2010–14844, and by the regional government of AndalucĂ­a through grant P09–FQM–4784.Peer Reviewe
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