Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.     

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.     

Pediatric Brain Tumors: Signatures from the Intact Proteome

The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma, pilocytic astrocytoma, and glioblastoma, in comparison with the available data on ependymoma, to contribute to the understanding of the molecular mechanisms underlying the onset and progression of these pathologies. Tissues have been homogenized in acidic water–acetonitrile solutions containing proteases inhibitors and analyzed by LC–high resolution MS for proteomic characterization and label-free relative quantitation. Tandem MS spectra have been analyzed by either manual inspection or software elaboration, followed by experimental/theoretical MS fragmentation data comparison by bioinformatic tools. Statistically significant differences in protein/peptide levels between the different tumor histotypes have been evaluated by ANOVA test and Tukey’s post-hoc test, considering a p-value > 0.05 as significant. Together with intact protein and peptide chains, in the range of molecular mass of 1.3–22.8 kDa, several naturally occurring fragments from major proteins, peptides, and proteoforms have been also identified, some exhibiting proper biological activities. Protein and peptide sequencing allowed for the identification of different post-translational modifications, with acetylations, oxidations, citrullinations, deamidations, and C-terminal truncations being the most frequently characterized. C-terminal truncations, lacking from two to four amino acid residues, particularly characterizing the β-thymosin peptides and ubiquitin, showed a different modulation in the diverse tumors studied. With respect to the other tumors, medulloblastoma, the most frequent malignant brain tumor of the pediatric age, was characterized by higher levels of thymosin β4 and β10 peptides, the latter and its des-IS form particularly marking this histotype. The distribution pattern of the C-terminal truncated forms was also different in glioblastoma, particularly underlying gender differences, according to the definition of male and female glioblastoma as biologically distinct diseases. Glioblastoma was also distinguished for the peculiar identification of the truncated form of the α-hemoglobin chain, lacking the C-terminal arginine, and exhibiting oxygen-binding and vasoconstrictive properties different from the intact form. The proteomic characterization of the undigested proteome, following the top-down approach, was challenging to originally investigate the post-translational events that differently characterize pediatric brain tumors. This study provides a contribution to elucidate the molecular profiles of the solid tumors most frequently affecting the pediatric age, and which are characterized by different grades of aggressiveness and localization.     

Disentangling Water Usage in the European Union: A Decomposition Analysis

The Water Framework Directive (WFD) defines common objectives for water resources throughout the European Union (EU). Given this general approach to water preservation and water policy, the objective of this paper is to analyse whether common patterns of water consumption exist within Europe. In particular, our study uses two methods to reveal the reasons behind sectoral water use in all EU countries. The first method is based on an accounting indicator that calculates the water intensity of an economy as the sum of sectoral water intensities. The second method is a subsystem input-output model that divides total water use into different income channels within the production system. The application uses data for the years 2005 and 2009 on water consumption in the production system of the 27 countries of the EU. From our analysis it emerges that EU countries are characterized by very different patterns of water consumption. In particular water consumption by the agriculture sector is extremely high in Central/Eastern Europe, relative to the rest of Europe. In most countries, the water used by the fuel, power and water sector is consumed to satisfy domestic final demand. However, our analysis shows that for some countries exports from this sector are an important driver of water consumption. Focusing on the agricultural sector, the decomposition analysis suggests that water usage in Mediterranean countries is mainly driven by final demand for, and exports of, agricultural products. In Central/Eastern Europe domestic final demand is the main driver of water consumption, but in this region the proportion of water use driven by demand for exports is increasing over time. Given these heterogeneous water consumption patterns, our analysis suggests that Mediterranean and Central/Eastern European countries should adopt specific water policies in order to achieve efficient levels of water consumption in the European Union.     

Poly(DL-lactide-co-ε-caprolactone) and poly(DL-lactide-co-glycolide) blends for biomedical application: Physical properties,cell compatibility,and in vitro degradation behavior

Poly(DL-lactide-co-ε-caprolactone) (PLCL) and poly(DL-lactide-co-glycolide) (PLGA) blends of various compositions were prepared. Fractured sections of PLCL/PLGA blends did not evidence phase separation and blend glass transition temperatures suggested some degree of blend compatibility. The elastic modulus showed a negative deviation from the additive law of mixture. Superior biocompatibility in terms of fibroblast NIH 3T3 cell adhesion and proliferation, better mechanical properties, and a more homogeneous phase were obtained with PLCL/PLGA 25/75 blend. Rapid degradation of PLCL phase (4–8 weeks) in PLCL/PLGA 25/75 blend led to a porous structure, which makes it a potential candidate for drug delivery systems.     

Influence of mineral additions on the performance of 100% recycled aggregate concrete

A judicious use of resources, by using by-products and waste materials, and a lower environmental impact, by reducing carbon dioxide emission and virgin aggregate extraction, allow to approach sustainable building development. Recycled aggregate concrete (RAC) containing supplementary cementitious materials (SCM), if satisfactory concrete properties are achieved, can be an example of such sustainable construction materials.In this work concrete specimens were manufactured by completely replacing fine and coarse aggregates with recycled aggregates from a rubble recycling plant. Also RAC with fly ash (RA + FA) or silica fume (RA + SF) were studied.Concrete properties were evaluated by means of compressive strength and modulus of elasticity in the first experimental part. In the second experimental part, compressive and tensile splitting strength, dynamic modulus of elasticity, drying shrinkage, reinforcing bond strength, carbonation, chloride penetration were studied. Satisfactory concrete properties can be developed with recycled fine and coarse aggregates with proper selection and proportioning of the concrete materials.     

Mapping the development of Open Access in Latin America and Caribbean countries. An analysis of Web of Science Core Collection and SciELO Citation Index (2005–2017)

Scientometrics - Open Access (OA) initiatives and knowledge infrastructure represent vital elements for both producing significant changes in scholarly communication and reducing limitations of...     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus).

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses