Characterisation and expression of β1-, β2- and β3-adrenergic receptors in the fathead minnow (Pimephales promelas)

This is the author’s version of a work that was accepted for publication in General and Comparative Endocrinology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published and may be accessed at the link below. Copyright © 2011 Elsevier B.V. All rights reserved.Complimentary DNAs for three beta-adrenergic receptors (βARs) were isolated and characterised in the fathead minnow. The encoded proteins of 402 (β(1)AR), 397 (β(2)AR) and 434 (β(3)AR) amino acids were homologous to other vertebrate βARs, and displayed the characteristic seven transmembrane helices of G Protein-coupled receptors. Motifs and amino acids shown to be important for ligand binding were conserved in the fathead minnow receptors. Quantitative RT-PCR revealed the expression of all receptors to be highest in the heart and lowest in the ovary. However, the β(1)AR was the predominant subtype in the heart (70%), and β(3)AR the predominant subtype in the ovary (53%). In the brain, β(1)AR expression was about 200-fold higher than that of β(2)- and β(3)AR, whereas in the liver, β(2)AR expression was about 20-fold and 100-fold higher than β(3)- and β(1)AR expression, respectively. Receptor gene expression was modulated by exposure to propranolol (0.001-1mg/L) for 21days, but not in a consistent, concentration-related manner. These results show that the fathead minnow has a beta-adrenergic receptor repertoire similar to that of mammals, with the molecular signatures required for ligand binding. An exogenous ligand, the beta-blocker propranolol, is able to alter the expression profile of these receptors, although the functional relevance of such changes remains to be determined. Characterisation of the molecular targets for beta-blockers in fish will aid informed environmental risk assessments of these drugs, which are known to be present in the aquatic environment.European Union as part of the ERAPharm project, Contract No. 511135 and NER

Analysis of the influence of under sleeper pads on the railway vehicle/track dynamic interaction in transition zones

[EN] Sharp changes in the vertical stiffness levels of a track can increase train and infrastructure deterioration to the point where there is a serious risk of a derailment. Major overloading and unloading forces are created between the different track and vehicle components. This phenomenon has grown in importance as the operational speeds of trains have increased with the expansion of high-speed lines. In order to solve this problem a method has to be found to smooth the changes in vertical stiffness levels along the track. In the present paper, the combination of transition regions and under- sleeper pads (USPs) has been studied. The research has been performed by means of a dynamic vehicle-track interaction model created by synthesizing a series of sub-models of individual effects. The analysed variables allow various track configurations, train travelling speeds and the stiffness of the USPs to be investigated. The obtained results show that combining transition zones with USPs pads allows more homogeneous vertical stiffness levels to be achieved along the tracks which results in improved dynamic behaviour of the vehicle-track system. © IMechE 2011.This work was supported by Ineco-Tifsa.Insa Franco, R.; Salvador Zuriaga, P.; Inarejos Mesa, J.; Roda Buch, A. (2012). Analysis of the influence of under sleeper pads on the railway vehicle/track dynamic interaction in transition zones. Proceedings of the Institution of Mechanical Engineers Part F Journal of Rail and Rapid Transit. 226(4):409-420. doi:10.1177/0954409711430174S409420226

Spitzer Observations of Interstellar Object 1I/`Oumuamua

1I/`Oumuamua is the first confirmed interstellar body in our Solar System. Here we report on observations of `Oumuamua made with the Spitzer Space Telescope on 2017 November 21--22 (UT). We integrated for 30.2~hours at 4.5 micron (IRAC channel 2). We did not detect the object and place an upper limit on the flux of 0.3 uJy (3sigma). This implies an effective spherical diameter less than [98, 140, 440] meters and albedo greater than [0.2, 0.1, 0.01] under the assumption of low, middle, or high thermal beaming parameter eta, respectively. With an aspect ratio for `Oumuamua of 6:1, these results correspond to dimensions of [240:40, 341:57, 1080:180] meters, respectively. We place upper limits on the amount of dust, CO, and CO2 coming from this object that are lower than previous results; we are unable to constrain the production of other gas species. Both our size and outgassing limits are important because `Oumuamua's trajectory shows non-gravitational accelerations that are sensitive to size and mass and presumably caused by gas emission. We suggest that `Oumuamua may have experienced low-level post-perihelion volatile emission that produced a fresh, bright, icy mantle. This model is consistent with the expected eta value and implied high albedo value for this solution, but, given our strict limits on CO and CO2, requires another gas species --- probably H2O --- to explain the observed non-gravitational acceleration. Our results extend the mystery of `Oumuamua's origin and evolution

Carbamazepine-Induced Tics

A variety of movement disorders are known to occur in association with carbamazepine (CBZ) therapy in adults and children, but development of tics has been described infrequently and only in patients with underlying Tourette's syndrome or other movement disorders. We report 3 children with epilepsy who developed facial motor tics after initiation of CBZ for complex partial seizures. All 3 had documented CBZ blood levels in the therapeutic range at the time, and none had other symptoms or signs of clinical intoxication. Neurologic examinations were normal in 2 and showed developmental de lay of expressive language in the third. Brain imaging was normal in all. After development of the tics in 2, CBZ was continued at the same or higher dose, and the tics abated and then ceased spontaneously ≤6 months. In the third child, the tics ceased after CBZ discontinuation. These cases demonstrate that CBZ can induce simple motor tics in children. These idiosyncratic reactions may be transient and do not always necessitate drug discontinuation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66313/1/j.1528-1157.1993.tb02119.x.pd

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Quality control for next-generation liquefaction case histories

The Next-Generation Liquefaction (NGL) database is an open-source, global database of liquefaction and non-ground failure case-histories. The database is part of a multi-year research effort with the main goal of developing improved procedures to evaluate liquefaction susceptibility, triggering, and consequences. In NGL, a case-history is defined as the intersection of three components: (1) a site, (2) an earthquake event, and (3) post-earthquake observations. The NGL database hosts case-histories used to develop existing liquefaction models, as well as new data derived from recent earthquakes such as the 2010-2011 Canterbury earthquake sequence, the 2011 Tohoku-Oki earthquake, and the 2012 Emilia earthquake. The database also hosts lateral spread case-histories, and a substantial number of liquefaction sites characterized by the presence of co-located recording stations. All of the data present in the NGL database are reviewed by the NGL Database Working Group. The NGL formal vetting process is described for an example case-history

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses

Investigating the effects of external fields polarization on the coupling of pure magnetic waves in the human body in very low frequencies

In this paper we studied the effects of external fields' polarization on the coupling of pure magnetic fields into human body. Finite Difference Time Domain (FDTD) method is used to calculate the current densities induced in a 1 cm resolution anatomically based model with proper tissue conductivities. Twenty different tissues have been considered in this investigation and scaled FDTD technique is used to convert the results of computer code run in 15 MHz to low frequencies which are encountered in the vicinity of industrial induction heating and melting devices. It has been found that external magnetic field's orientation due to human body has a pronounced impact on the level of induced currents in different body tissues. This may potentially help developing protecting strategies to mitigate the situations in which workers are exposed to high levels of external magnetic radiation

Analysis of the backward bending modes in damped rotating beams

[EN] This article presents a study of the backward bending mode of a simply supported rotating Rayleigh beam with internal damping. The study analyses the natural frequency behaviour of the backward mode according to the internal viscous damping ratio, the slenderness of the beam and its spin speed. To date, the behaviour of the natural frequency of the backward mode is known to be a monotonically decreasing function with spin speed due to gyroscopic effects. In this article, however, it is shown that this behaviour of the natural frequency may not hold for certain damping and slenderness conditions, and reaches a minimum value (concave function) from which it begins to increase. Accordingly, the analytical expression of the spin speed for which the natural frequency of the backward mode attains the minimum value has been obtained. In addition, the internal damping ratio and slenderness intervals associated with such behaviour have been also provided.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors gratefully acknowledge the financial support of Ministerio de Ciencia, Innovacion y Universidades Agencia Estatal de Investigacion and the European Regional Development Fund (project TRA2017-84701-R), as well as Generalitat Valenciana (project Prometeo/2016/007) and European Commission through the project 'RUN2Rail - Innovative RUNning gear soluTiOns for new dependable, sustainable, intelligent and comfortable RAIL vehicles' (Horizon 2020 Shift2Rail JU call 2017, grant number 777564)Martínez Casas, J.; Denia Guzmán, FD.; Fayos Sancho, J.; Nadal, E.; Giner Navarro, J. (2019). Analysis of the backward bending modes in damped rotating beams. Advances in Mechanical Engineering. 11(4):1-13. https://doi.org/10.1177/1687814019840474S113114Zorzi, E. S., & Nelson, H. D. (1977). Finite Element Simulation of Rotor-Bearing Systems With Internal Damping. Journal of Engineering for Power, 99(1), 71-76. doi:10.1115/1.3446254Ku, D.-M. (1998). FINITE ELEMENT ANALYSIS OF WHIRL SPEEDS FOR ROTOR-BEARING SYSTEMS WITH INTERNAL DAMPING. Mechanical Systems and Signal Processing, 12(5), 599-610. doi:10.1006/mssp.1998.0159Dimentberg, M. F. (2005). Vibration of a rotating shaft with randomly varying internal damping. Journal of Sound and Vibration, 285(3), 759-765. doi:10.1016/j.jsv.2004.11.025Vatta, F., & Vigliani, A. (2008). Internal damping in rotating shafts. Mechanism and Machine Theory, 43(11), 1376-1384. doi:10.1016/j.mechmachtheory.2007.12.009Rosales, M. B., & Filipich, C. P. (1993). Dynamic Stability of a Spinning Beam Carrying an Axial Dead Load. Journal of Sound and Vibration, 163(2), 283-294. doi:10.1006/jsvi.1993.1165Mazzei, A. J., & Scott, R. A. (2003). Effects of internal viscous damping on the stability of a rotating shaft driven through a universal joint. Journal of Sound and Vibration, 265(4), 863-885. doi:10.1016/s0022-460x(02)01256-7Ehrich, F. F. (1964). Shaft Whirl Induced by Rotor Internal Damping. Journal of Applied Mechanics, 31(2), 279-282. doi:10.1115/1.3629598Vance, J. M., & Lee, J. (1974). Stability of High Speed Rotors With Internal Friction. Journal of Engineering for Industry, 96(3), 960-968. doi:10.1115/1.3438468Vila, P., Baeza, L., Martínez-Casas, J., & Carballeira, J. (2014). Rail corrugation growth accounting for the flexibility and rotation of the wheel set and the non-Hertzian and non-steady-state effects at contact patch. Vehicle System Dynamics, 52(sup1), 92-108. doi:10.1080/00423114.2014.881513Glocker, C., Cataldi-Spinola, E., & Leine, R. I. (2009). Curve squealing of trains: Measurement, modelling and simulation. Journal of Sound and Vibration, 324(1-2), 365-386. doi:10.1016/j.jsv.2009.01.048Bauer, H. F. (1980). Vibration of a rotating uniform beam, part I: Orientation in the axis of rotation. Journal of Sound and Vibration, 72(2), 177-189. doi:10.1016/0022-460x(80)90651-3Shiau, T. N., & Hwang, J. L. (1993). Generalized Polynomial Expansion Method for the Dynamic Analysis of Rotor-Bearing Systems. Journal of Engineering for Gas Turbines and Power, 115(2), 209-217. doi:10.1115/1.2906696Hili, M. A., Fakhfakh, T., & Haddar, M. (2006). Vibration analysis of a rotating flexible shaft–disk system. Journal of Engineering Mathematics, 57(4), 351-363. doi:10.1007/s10665-006-9060-3Young, T. H., Shiau, T. N., & Kuo, Z. H. (2007). Dynamic stability of rotor-bearing systems subjected to random axial forces. Journal of Sound and Vibration, 305(3), 467-480. doi:10.1016/j.jsv.2007.04.016Wang, J., Hurskainen, V.-V., Matikainen, M. K., Sopanen, J., & Mikkola, A. (2017). On the dynamic analysis of rotating shafts using nonlinear superelement and absolute nodal coordinate formulations. Advances in Mechanical Engineering, 9(11), 168781401773267. doi:10.1177/1687814017732672Lee, C.-W. (1993). Vibration Analysis of Rotors. Solid Mechanics and Its Applications. doi:10.1007/978-94-015-8173-8Genta, G. (1999). Vibration of Structures and Machines. doi:10.1007/978-1-4612-1450-2Cheng, C. C., & Lin, J. K. (2003). Modelling a rotating shaft subjected to a high-speed moving force. Journal of Sound and Vibration, 261(5), 955-965. doi:10.1016/s0022-460x(02)01374-

Identification and evaluation of risk of generalizability biases in pilot versus efficacy/effectiveness trials: A systematic review and meta-analysis

Background: Preliminary evaluations of behavioral interventions, referred to as pilot studies, predate the conduct of many large-scale efficacy/effectiveness trial. The ability of a pilot study to inform an efficacy/effectiveness trial relies on careful considerations in the design, delivery, and interpretation of the pilot results to avoid exaggerated early discoveries that may lead to subsequent failed efficacy/effectiveness trials. “Risk of generalizability biases (RGB)” in pilot studies may reduce the probability of replicating results in a larger efficacy/effectiveness trial. We aimed to generate an operational list of potential RGBs and to evaluate their impact in pairs of published pilot studies and larger, more well-powered trial on the topic of childhood obesity. Methods: We conducted a systematic literature review to identify published pilot studies that had a published larger-scale trial of the same or similar intervention. Searches were updated and completed through December 31st, 2018. Eligible studies were behavioral interventions involving youth (≤18 yrs) on a topic related to childhood obesity (e.g., prevention/treatment, weight reduction, physical activity, diet, sleep, screen time/sedentary behavior). Extracted information included study characteristics and all outcomes. A list of 9 RGBs were defined and coded: intervention intensity bias, implementation support bias, delivery agent bias, target audience bias, duration bias, setting bias, measurement bias, directional conclusion bias, and outcome bias. Three reviewers independently coded for the presence of RGBs. Multi-level random effects meta-analyses were performed to investigate the association of the biases to study outcomes. Results: A total of 39 pilot and larger trial pairs were identified. The frequency of the biases varied: delivery agent bias (19/39 pairs), duration bias (15/39), implementation support bias (13/39), outcome bias (6/39), measurement bias (4/39), directional conclusion bias (3/39), target audience bias (3/39), intervention intensity bias (1/39), and setting bias (0/39). In meta-analyses, delivery agent, implementation support, duration, and measurement bias were associated with an attenuation of the effect size of − 0.325 (95CI − 0.556 to − 0.094), − 0.346 (− 0.640 to − 0.052), − 0.342 (− 0.498 to − 0.187), and − 0.360 (− 0.631 to − 0.089), respectively. Conclusions Pre-emptive avoidance of RGBs during the initial testing of an intervention may diminish the voltage drop between pilot and larger efficacy/effectiveness trials and enhance the odds of successful translation