The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.     

Explicit versus implicit method for radiative heat transfer in gray and diffuse enclosures

The paper presents an explicit formulation of the radiative problem in gray enclosures. The method is based on a series expansion that derives the mutual radiation factors by means of summation of the contributions to the radiative thermal exchange given by the multi-reflection process. A mathematical proof that the infinite expansion converges to the well known solution, given by the implicit formulation and based on radiosities balance, is provided. Moreover a parametric analysis of the approximation induced by the explicit algorithm, as a result of the truncation order in the calculation of the series expansion, is carried out. The analysis shows how the precision of every approximation order is mainly related to the surface averaged infrared reflectance and is weakly dependent on the reflectance distribution. For high emissive and low reflecting surfaces, very few summations are required to meet high precision; the same level of precision is achievable also with medium and high reflecting surfaces, by increasing the truncation order of the series. More generally, the explicit formulation provides an alternative approach to problems involving multi-reflecting cavities in different engineering applications, from heat transfer to optics.     

Optimization of the procedure to burn textile fabrics by cone calorimeter: Part I. Combustion behavior of polyester

The aim of this study was the optimization of cone calorimeter to determine the burning behavior of textile fabrics. In particular, the combustion behavior of commercial polyester textile fabrics with varying densities was studied in terms of time to ignition (TTI), heat release rate (HRR), and relative peak (pkHRR) were monitored. Reproducibility and repeatability of the data have been verified by the influence of instrument variable including incident heat flux, the temperature of ceramic backing pads and retaining grid used during sample mounting as well as sample weight (as the number of fabric layers), the density of textiles, and the relative humidity. A low reproducibility has been obtained when a wire grid was not used to stabilize samples during the tests. The effects of these variables on TTI and pkHRR were observed. Copyright © 2010 John Wiley & Sons, Ltd.     

An automatic procedure for the synthesis and optimization of very low-frequency Gm–C integrators

Fully integrated low frequency filters are critical cells that should be carefully designed in order to avoid excessive area occupation. In this work we propose an automatic procedure capable of optimizing the design of G_m?CC integrators, which constitute the basis of a wide class of G_m?CC filters. The optimization target is minimizing the cell area with constraints on input range and low frequency noise. Lower and upper bounds can be fixed to most quantities and design parameters in order to avoid solutions that are not compatible with the physical limitations of the process. The program has been developed within the MATLAB^? platform, exploiting the optimization toolbox. The effect of several important design parameters on the optimization of low frequency integrators has been investigated using the proposed routine. The strong interaction between noise and low frequency constraints has been demonstrated, showing the impressive impact of strict noise specifications on the occupied area. The actual effectiveness of parameters such as the current division factor or approaches such as flicker noise rejection by means of chopper modulation has been investigated. Examples of integrator synthesis, performed using the proposed procedure configured with the parameters of a commercial CMOS process, are presented. The consistence between the characteristics of the cells and the initial specifications has been checked using electrical simulations showing a maximum discrepancy with the initial specifications of nearly 80%. A semi-manual method to refine the synthesized cells and improve the accuracy is proposed.     

Multi-agent quality of experience control

International Journal of Control, Automation and Systems - In the framework of the Future Internet, the aim of the Quality of Experience (QoE) Control functionalities is to track the personalized...