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.     

ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (q-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and p-value = 9.6 × 10⁻⁶) and non-lobar ICH (z-score = −4.8 and p-value = 1.58 × 10⁻⁶) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (p-value = 3.66 × 10⁻⁵) and non-lobar ICH (p-value = 1.81 × 10⁻⁵). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.     

Multifunctional biomagnetic capsules for easy removal of phenol and bisphenol A

This paper reports fabrication, optimization and characterization of multifunctional biocapsules with immobilized enzyme using a layer-by-layer configuration and their application for removal of phenol and bisphenol A (BPA). The method is based on the combined use of enzymatic oxidation of the BPA and subsequent binding of the reaction product onto a chitosan core biopolymer. This platform has multiple functions including: (1) enzymatic degradation of BPA, (2) adsorption of the degraded compound within the core material, (3) colorimetric quantification and (4) magnetic capabilities. We examined various configurations of core/shell structures of alginate and chitosan and determined the stability and the optimum conditions in which these structures provide the most effective removal capacity. The amount of BPA that can be removed per capsule is 5.6 ppm while phenol can be removed up to 10 ppm per capsule within 15 h.     

College students’ social justice interest and commitment: A social-cognitive perspective.

In this study, the authors examined the degree to which social-cognitive career theory (SCCT; R. W. Lent, S. D. Brown, & G. Hackett, 1994) explained the development of social justice interest and commitment. Data from 274 college students and latent variable path modeling were used to test theoretically and empirically derived SCCT direct and indirect effects structural models. The direct effects model estimated the direct effect of social supports and barriers on social justice commitment and the indirect effects model estimated the effect of social supports and barriers indirectly through self-efficacy. Overall, the present findings supported the use of SCCT within the social justice domain, as social justice self-efficacy and outcome expectations were useful in explaining the development of college students’ social justice interest and commitment. The present findings supported the indirect effects model of social justice interest and commitment over the direct effects model. Finally, unique to prior tests of SCCT in vocational and academic domains, social supports and barriers exhibited an indirect effect on commitment through outcome expectations. Study limitations, future directions for research, and implications for facilitating college students’ social justice interest and commitment are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Optimization of a slurry dispersion method for minerals and trace elements analysis in infant formulae by ICP OES and FAAS

Infant formula developed by manufacturers requires a rigorous control of composition, particularly those elements added routinely in an attempt to mimic the mineral composition of human milk. A total of 97 different types of powdered infant formulae (preterm, adapted starter, adapted follow-up, toddler, specialised and soy-based formulae) commercially available in Spain were studied. It is noteworthy great differences in mineral (Ca, P, Mg) and trace element (Zn, Fe, Cu, Mn) contents found between analysed and listed in label information. The development of a fast, simple and direct slurry method for the determination of these essential micronutrients in infant formula by inductively coupled plasma optical emission spectrometry (ICP OES) and flame atomic absorption spectrometry (FAAS) was performed in order to help in quality control tasks. Infant formula samples were solubilised using different amounts of several different solvents. An addition of 250 μL of a solution 10% tetramethylammonium hydroxide and 25% ammonium hydroxide were required for the accurate quantification of Ca and P, Mg, Zn, Fe, Cu and Mn, respectively. The standard reference material 1549 non-fat milk powder was solubilised to compare the validity of assayed methodology following slurry nebulisation and traditional microwave-assisted acid digestion method. Good agreement of the analytical results by both ICP OES and FAAS, with the certified values was obtained. Method performance parameters (accuracy, precision and methodological detection limits) were determined for studied elements to check the quality and usefulness of the optimised slurry method. The analytical procedure was applied successfully to the analysis of a representative group of infant formulae. Levels of analysed elements were graphically represented, showing an acceptable comparability between slurry and acid-mineralisation method set by linear correlation coefficients and slopes close to the unit. The described simple and slurry method is appropriate, as an attractive alternative, for routine control analysis of added essential elements in infant formulae regardless of predominant protein type used in manufacture.     

Exoglucanase‐encoding genes from three Wickerhamomyces anomalus killer strains isolated from olive brine

Wickerhamomyces anomalus killer strains are important for fighting pathogenic yeasts and for controlling harmful yeasts and bacteria in the food industry. Targeted disruption of key genes in β‐glucan synthesis of a sensitive Saccharomyces cerevisiae strain conferred resistance to the toxins of W. anomalus strains BS91, BCA15 and BCU24 isolated from olive brine. Competitive inhibition of the killing activities by laminarin and pustulan refer to β‐1,3‐ and β‐1,6‐glucans as the main primary toxin targets. The extracellular exoglucanase‐encoding genes WaEXG1 and WaEXG2 from the three strains were sequenced and were found to display noticeable similarities to those from known potent W. anomalus killer strains. Accession Nos for WaEXG1 genes for the strains in brackets are JQ734563 (BS91), JQ734564 (BCA15) and JQ734565 (BCU24); for WaEXG2 genes JQ734566 (BS91), JQ734567 (BCA15) and JQ734568 (BCU24), respectively. Copyright © 2012 John Wiley & Sons, Ltd.     

Evaluation of a screening method for classifying virgin and recycled paper and board samples

This paper deals with the study of volatile compounds released by recycled paper and board. The aim of the study was to demonstrate the feasibility of headspace procedure coupled to gas chromatography/mass spectrometry (GC/MS) applied to complex paper‐based samples together with a chemometric procedure as a powerful method for screening potential volatile contaminants released by the recycled and virgin paper samples. Using this procedure, the identification of virgin or recycled paper could be achieved based on the identification on specific markers of the recycled pulp. Fifteen different samples within virgin and recycled paper were studied. After equilibration, the vapour phase of the samples was analysed by automatic headspace coupled online to GC/MS. The analytical approach for volatile compounds, their identification and the selection of some compounds as markers for recycled pulp are shown and discussed. A discriminate analysis applied to the set of results obtained allows classification of the samples into four different groups according to the content of recycled pulp (0, 10–30 and > 80% of recycled pulp), the surface treatment of the paper (no surface treatment, clay coating and plastic coating), the grammage (from < 100 to > 300 g/m²) and the sample thickness (from < 300 to > 600 µm). The matrix effect on the volatilization of some compounds from the paper samples and the analytical behaviour are also discussed. Copyright © 2009 John Wiley & Sons, Ltd.