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.     

Electrochemical reduction of oxygen on thin-film Pt electrodes in acid solutions

The electrochemical reduction of oxygen on thin-film platinum electrodes in 0.1 M HClO₄ and 0.05 M H₂SO₄ solutions has been investigated using the rotating disk electrode (RDE) method. Thin films of Pt (0.25-20 nm thick) were prepared by vacuum evaporation onto glassy carbon substrate. The surface morphology of Pt films was examined by transmission electron microscopy (TEM). The specific activity of O₂ reduction was higher in HClO₄ and decreased with decreasing film thickness. In H₂SO₄, the specific activity was lower and appeared to be independent of the Pt loading. The values of Tafel slopes close to −120 mV dec⁻¹ in high current density range and −60 mV dec⁻¹ in low current density range were obtained for all electrodes in both solutions, indicating that the mechanism of O₂ reduction is the same for thin-film electrodes as for bulk Pt. The number of electrons transferred per O₂ molecule was close to four for all thin Pt films studied.     

Electrocatalysis of oxygen reduction by quinones adsorbed on highly oriented pyrolytic graphite electrodes

The reduction of oxygen in alkaline solution has been studied on highly oriented pyrolytic graphite (HOPG) electrodes modified with various quinones using a rotating disk electrode (RDE). The electrode surface was modified by adsorption of quinones from a 0.1 M KOH solution. The oxygen reduction activity of these electrodes was considerably higher than that for unmodified HOPG and characteristic current maxima for oxygen reduction was observed. All quinones studied catalysed the two-electron reduction of oxygen to hydrogen peroxide. The peak potentials for oxygen reduction were in good correlation with the redox potentials of the quinones that were found from the cyclic voltammograms in oxygen-free solutions. The results obtained give further evidence that oxygen reduction is catalysed by the semiquinone radical and that the redox potential of the quinone is the most important factor determining its electrocatalytic activity for oxygen reduction.     

Electrochemical reduction of oxygen on palladium nanocubes in acid and alkaline solutions

The electrocatalytic properties of cubic palladium nanoparticles towards the electrochemical reduction of oxygen were studied in acid and alkaline solutions and compared with those of spherical nanoparticles and bulk Pd. The synthesised Pd nanoparticles were characterised by transmission electron microscopy (TEM) and X-ray diffraction (XRD). Electrooxidation of pre-adsorbed CO was employed for cleaning the palladium catalyst surface. Oxygen reduction was studied using the rotating disk electrode (RDE) method and enhanced electrocatalytic activity of Pd nanocubes was revealed both in acid and alkaline solutions, which was attributed to the prevalence of Pd(1 0 0) facets. The mechanism of oxygen reduction on Pd nanoparticles was similar to that on bulk Pd, the first electron transfer being the rate-limiting step, and the reaction predominantly followed a four-electron pathway in both solutions.     

Electroreduction of oxygen on carbon-supported gold catalysts

The electrochemical reduction of oxygen was studied on Au/C catalysts (20 and 30 wt%) in 0.5 M H₂SO₄ and 0.1 M KOH solutions using the rotating disk electrode (RDE) method. The thickness of the Au/C–Nafion layers was varied between 1.5 and 10 μm. The specific activity of Au was independent of catalyst loading in both solutions, indicating that the transport of reactants through the catalyst layer does not limit the process of oxygen reduction under these conditions. The mass activity of 20 wt% Au/C catalysts was higher due to smaller particle size. The number of electrons involved in the reaction and the Tafel slopes were found; the values of these parameters are similar to that of bulk polycrystalline gold and indicate that the mechanism of O₂ reduction is not affected by carbon support or the catalyst configuration.     

Effects of drying on the gel strength and cation mobility of furcellaran

Thermal stability, by means of air drying a furcellaran powder, and its impact on gel strength and cation mobility were studied. Halogen heating in the temperature range 90–115°C for 15 min resulted in loss on drying (L_D, %). These results can be described by polynom L_D=−9.583+2.989τ−0.249τ²+0.00729τ³+0.1034t (R²=0.9976), indicating a gradual decomposition of carbohydrates. Air-drying induced a decrease in gel strength and the partial removal of potassium, calcium and sodium ions from the matrix. Air drying above 115°C yielded a remarkable destruction of polysaccharides with a total collapse in gelling power.     

Next-generation lithography for 22 and 16 nm technology nodes and beyond

In this paper, next-generation lithography (NGL) for the 22 and 16 nm technology nodes and beyond is reviewed. A broad range of topics, including history, technologies, critical challenges, and the most plausible candidates are discussed. The 22 and 16 nm technology nodes rely on NGL. NGLs have been extensively studied. Because of technological issues, the semiconductor industry has stopped pursuing several NGLs, such as X-ray proximity lithography, ion projection lithography, and scattering with angular li...     

Developing an effective support system for inquiry learning in a Web-based environment

Abstract Sixty-five teams of basic and secondary school students solved problem-solving tasks during a virtual hike in a Web-based inquiry-learning simulation 'Hiking Across Estonia'. This environment provided learners with all necessary background information for problem-solving and tools for carrying out experiments. There were 25 tasks in certain order about ecological and environmental issues. The teams were clustered according to the data about participants, the results of the pre- and post-test, and their achievement in problem-solving tasks of the virtual hike. Only two out of five clusters were regarded as effective in solving problems and analysing tables, graphs, figures, and photos. The others had difficulties in forming contextual or task and process awareness. A support system for increasing the effectiveness of inquiry learning and enhancing their development of analytical skills was developed on the basis of the strategies that the members of five clusters had used in solving the problems, their achievement in solving the tasks during the virtual hike and in the pre- and post-test, and the personal data about the teams. The support system contained different notes before solving the problems and changed sequence of the tasks on the virtual hike for some clusters. The usage of this system was evaluated in a second study with 60 teams. The comparison of two studies demonstrated significant effectiveness of the support system to both general problem-solving ability and analytical skills. The characteristics of each cluster and the influence of the support system are discussed in this paper.     

In defence of sublinguistics

The paper is a response to the argument presented by Jussi Karlgren that the term sublanguage involves a potentially damaging misunderstanding in human-computer interaction research. The use of the term in the context of a mathematical concept of language as a set is defended. The definition of language in terms of probability and the use of domain context to condition probabilities is suggested as a refinement to this concept.     

Electroreduction of oxygen on sputter-deposited Pd nanolayers on multi-walled carbon nanotubes

The electrochemical reduction of oxygen on Pd nanoparticle/multi-walled carbon nanotube (PdNP/MWCNT) catalysts was studied in acid and alkaline solutions using the rotating disk electrode (RDE) method. The PdNP/MWCNT nanocomposites were prepared by sputter-deposition of palladium onto the surface of MWCNTs. The surface morphology of the PdNP/MWCNT composites was characterised by scanning electron microscopy (SEM). The SEM images showed the formation of Pd nanolayers around MWCNTs. The RDE results revealed a high electrocatalytic activity of PdNP/MWCNT catalysts towards the oxygen reduction reaction (ORR) in alkaline media. Two Tafel regions with different slope can be distinguished. At low overpotentials the Tafel slope is close to −60 mV dec⁻¹ and at higher current densities the slope is approximately −100 mV dec⁻¹. The PdNP/MWCNT composite is a promising material to be used as a cathode catalyst for alkaline membrane fuel cells.