Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.

Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states

Operating a full tungsten actively cooled tokamak: overview of WEST first phase of operation

WEST is an MA class superconducting, actively cooled, full tungsten (W) tokamak, designed to operate in long pulses up to 1000 s. In support of ITER operation and DEMO conceptual activities, key missions of WEST are: (i) qualification of high heat flux plasma-facing components in integrating both technological and physics aspects in relevant heat and particle exhaust conditions, particularly for the tungsten monoblocks foreseen in ITER divertor; (ii) integrated steady-state operation at high confinement, with a focus on power exhaust issues. During the phase 1 of operation (2017–2020), a set of actively cooled ITER-grade plasma facing unit prototypes was integrated into the inertially cooled W coated startup lower divertor. Up to 8.8 MW of RF power has been coupled to the plasma and divertor heat flux of up to 6 MW m−2 were reached. Long pulse operation was started, using the upper actively cooled divertor, with a discharge of about 1 min achieved. This paper gives an overview of the results achieved in phase 1. Perspectives for phase 2, operating with the full capability of the device with the complete ITER-grade actively cooled lower divertor, are also described

Survival analysis: A consumer-friendly method to estimate the optimum sucrose level in probiotic petit suisse

For years, just-about-right (JAR) scales have been among the most used techniques to obtain sensory information about consumer perception, but recently, some researchers have harshly criticized the technique. The present study aimed to apply survival analysis to estimate the optimum sucrose concentration in probiotic petit suisse cheese and compare the survival analysis to JAR scales to verify which technique more accurately predicted the optimum sucrose concentration according to consumer acceptability. Two panels of consumers (total = 170) performed affective tests to determine the optimal concentration of sucrose in probiotic petit suisse using 2 different methods of analysis: JAR scales (n = 85) and survival analysis (n = 85). Then an acceptance test was conducted using naïve consumers (n = 100) between 18 and 60 yr old, with 2 samples of petit suisse, one with the ideal sucrose determined by JAR scales and the other with the ideal sucrose content determined by survival analysis, to determine which formulation was in accordance with consumer acceptability. The results indicate that the 2 sensory methods were equally effective in predicting the optimum sucrose level in probiotic petit suisse cheese, and no significant differences were detected in any of the characteristics related to liking evaluated. However, survival analysis has important advantages over the JAR scales. Survival analysis has shown the potential to be an advantageous tool for dairy companies because it was able to accurately predict the optimum sucrose content in a consumer-friendly way and was also practical for researchers because experimental sensory work is simpler and has been shown to be more cost effective than JAR scales without losses of consumer acceptability.Fil: Esmerino, E. A.. Universidade Estadual de Campinas; BrasilFil: Paixão, J. A.. Universidade Estadual de Campinas; BrasilFil: Cruz, A. G.. Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro; BrasilFil: Garitta, Lorena Garitta. Provincia de Buenos Aires. Dirección General de Cultura y Educación. Instituto Superior Experimental de Tecnología Alimentaria. Departamento de Evaluación Sensorial de Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hough, Guillermo. Provincia de Buenos Aires. Dirección General de Cultura y Educación. Instituto Superior Experimental de Tecnología Alimentaria. Departamento de Evaluación Sensorial de Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bolini, H. M. A.. Universidade Estadual de Campinas; Brasi

First Flight Escape Probability and Uncollided Flux of Nuclear Particles in Convex Bodies with Spherical Symmetry

This paper deals with the evaluation of the first flight escape probability of nuclear particles from convex bodies with spherical symmetry by means of some geometrical arguments and very simple probability considerations. The cases of a full sphere, a one-region spherical shell with an empty central zone, a spherical shell region containing a black central zone, and a full sphere with a sourceless shell have been considered. In all the aforementioned cases, a homogeneous medium and uniform isotropic source have been taken into account. Moreover, a simple and general formula has been derived for the calculation of the uncollided flux that is presupposed to be valid for arbitrary geometries. The results obtained have been validated by Monte Carlo analyses performed by the Monte Carlo N-Particle (MCNP5) code and critically discussed

First Flight Escape Probability and Uncollided Flux of Nuclear Particles in Convex Bodies with Spherical Symmetry

This paper deals with the evaluation of the first flight escape probability of nuclear particles from convex bodies with spherical symmetry by means of some geometrical arguments and very simple probability considerations. The cases of a full sphere, a one-region spherical shell with an empty central zone, a spherical shell region containing a black central zone, and a full sphere with a sourceless shell have been considered. In all the aforementioned cases, a homogeneous medium and uniform isotropic source have been taken into account. Moreover, a simple and general formula has been derived for the calculation of the uncollided flux that is presupposed to be valid for arbitrary geometries. The results obtained have been validated by Monte Carlo analyses performed by the Monte Carlo N-Particle (MCNP5) code and critically discussed

Hydraulic analysis of EU-DEMO divertor plasma facing components cooling circuit under nominal operating scenarios

Within the framework of the Work Package DIV 1 – “Divertor Cassette Design and Integration” of the EUROfusion action, a research campaign has been jointly carried out by University of Palermo and ENEA to investigate the steady state thermal-hydraulic behaviour of the DEMO divertor cassette cooling circuit, focussing the attention on its Plasma Facing Components (PFCs). The research campaign has been carried out following a theoretical-computational approach based on the Finite Volume Method and adopting the commercial Computational Fluid-Dynamic code ANSYS-CFX. A realistic model of the PFCs cooling circuit has been analysed, specifically embedding each Plasma Facing Unit (PFU) cooling channel with the foreseen swirl tape turbulence promoter, hence resulting in a finite volume model much more detailed than those assessed in previous analyses. Its thermal-hydraulic performances have been numerically evaluated under nominal steady state conditions, also comparing the obtained results with the corresponding outcomes of analogous analyses carried out for a simplified PFCs configuration, without swirl tapes. Moreover, the main thermal-hydraulic parameters have been evaluated in order to check whether the considered PFCs cooling circuit might fulfil the total pressure drop requirement (Δp <1.4 MPa), providing a uniform cooling of the Vertical Target PFU channels with a viable CHF margin (>1.4). The PFCs cooling circuit thermal-hydraulic behaviour has been additionally assessed at alternative operative conditions, issued to check the viability of a coolant velocity reduction, in order to minimize corrosion and vibrations inside the PFU channels. Models, loads and boundary conditions assumed for the analyses are herewith reported and critically discussed, together with the main results obtained