Galectin‐3‐Binding Glycomimetics that Strongly Reduce Bleomycin‐Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition

Discovery of glycan‐competitive galectin‐3‐binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin‐3 accumulation at damaged vesicles, hence revealing galectin‐3–glycan interactions involved in fibrosis progression and in intracellular galectin‐3 activities, is reported. 3,3′‐Bis‐(4‐aryltriazol‐1‐yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin‐1, ‐2, ‐3, and ‐4 N‐terminal, ‐4 C‐terminal, ‐7 and ‐8 N‐terminal, ‐9 N‐terminal, and ‐9 C‐terminal domains. Compounds displaying low‐nanomolar affinities for galectins‐1 and ‐3 were identified in a competitive fluorescence anisotropy assay. X‐ray structural analysis of selected compounds in complex with galectin‐3, together with galectin‐3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin‐3. The most potent galectin‐3 antagonist was demonstrated to act in an assay monitoring galectin‐3 accumulation upon amitriptyline‐induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin–carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin‐induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.     

Highly sensitive PCR-based detection method specific for Aspergillus flavus in wheat flour

Aspergillus flavus is frequently found in food, producing a wide variety of toxins, aflatoxins being the most relevant in food safety. A specific PCR-based protocol for this species is described which allowed discrimination from other closely related species having different profiles of secondary metabolites from the Aspergillus Section Flavi, particularly A. parasiticus. The specific primers were designed on the multi-copy internal transcribed region of the rDNA unit (ITS1-5.8S-ITS2 rDNA) and were tested in a wide sample of related species and other fungal species commonly found in food. The PCR assay was coupled with a fungal enrichment and a DNA extraction method for wheat flour to enhance the sensitivity of the diagnostic protocol. The results indicated that the critical PCR amplification product was clearly observed for wheat flour contaminated by 10² spores after 16 h of incubation.     

Activation of the Interleukin-33/ST2 Pathway Exerts Deleterious Effects in Myxomatous Mitral Valve Disease

Mitral valve disease (MVD) is a frequent cause of heart failure and death worldwide, but its etiopathogenesis is not fully understood. Interleukin (IL)-33 regulates inflammation and thrombosis in the vascular endothelium and may play a role in the atherosclerotic process, but its role in mitral valve has not been investigated. We aim to explore IL-33 as a possible inductor of myxomatous degeneration in human mitral valves. We enrolled 103 patients suffering from severe mitral regurgitation due to myxomatous degeneration undergoing mitral valve replacement. Immunohistochemistry of the resected leaflets showed IL-33 and ST2 expression in both valve interstitial cells (VICs) and valve endothelial cells (VECs). Positive correlations were found between the levels of IL-33 and molecules implicated in the development of myxomatous MVD, such as proteoglycans, extracellular matrix remodeling enzymes (matrix metalloproteinases and their tissue inhibitors), inflammatory and fibrotic markers. Stimulation of single cell cultures of VICs and VECs with recombinant human IL-33 induced the expression of activated VIC markers, endothelial–mesenchymal transition of VECs, proteoglycan synthesis, inflammatory molecules and extracellular matrix turnover. Our findings suggest that the IL-33/ST2 system may be involved in the development of myxomatous MVD by enhancing extracellular matrix remodeling.     

Definition of requirements for accessing multilingual information opinions

Multimedia Tools and Applications - In this paper, we will present a study concerning the understanding of the needs of people using Internet in order to access to multilingual information. In...     

Production planning under a working time accounts scheme

Working time accounts (WTAs) provide flexibility to a company to adjust the capacity to the demand by planning, for each period and each worker, an appropriate number of working hours. Under this scheme, every worker has a balance that can be positive (the company owes hours to the worker), zero or negative (the worker owes hours to the company). Credit (or debit) hours are compensated by working less (or more) hours than the reference value in the subsequent periods. This scheme is especially useful for companies dealing with demand fluctuations, because WTA balances can take any value, provided that these belong to a given bounded interval. Other conditions that affect the number and distribution of working hours may be established either in law or in the WTA agreement. This paper proposes a new mathematical model for planning production, inventory levels, working time and temporary closures in a manufacturing company operating under a standard WTA scheme. The results of the computational study show that the model is an appropriate tool not only for planning but also for helping in the bargaining process (different WTA scheme configurations could be evaluated with the model).     

Optimization of Focused Ultrasound Extraction and Supercritical Fluid Extraction of Volatile Compounds and Antioxidants from Aromatic Plants

In this work, we have accomplished the optimization of focused ultrasound extraction and supercritical fluid extraction (SFE) of volatile oils and phenolic compounds from aromatic plants such as rosemary, oregano, and chamomile. The response surface analysis was the overall procedure to tackle this work. On the one hand, the focused ultrasound extraction method of volatile compounds was studied based on the use of cyclohexane as extractant (chamomile required cyclohexane:isopropanol (95:5)), and three parameters were optimized (cycles, amplitude, and time) for each plant. The quantification of the volatile compounds was performed by means of GC?×?GC-MS analysis and the volatile oil concentration rounded 10–310 μg/g for the oregano; 7–2,920 μg/g for the rosemary, and 0.8–244.2 mg/g for the chamomile. In the SFE method, four parameters were studied (oven temperature, pressure, CO₂ flow, and EtOH?%). The total polyphenol content was determined by Folin–Ciocalteu obtaining values from 1,000 to 12,000 mg gallic acid equivalent (GAE)/g plant. The antioxidant capacity was measured by Trolox equivalent antioxidant capacity obtaining values from 1.1 to 46.7 μmol Trolox equivalent/g plant.     

Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl₂ treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.     

Precipitation of Nb in Ferrite After Austenite Conditioning. Part II: Strengthening Contribution in High-Strength Low-Alloy (HSLA) Steels

Often, Nb contributes to the strength of a microalloyed steel beyond the expected level because of the grain size strengthening resulting from thermomechanical processing. Two different mechanisms are behind this phenomenon, and both of them have to do with the amount of Nb remaining in solution after hot rolling. The first of them is the increase of the hardenability of the steel as a result of Nb, and the second one is the fine precipitation of NbC in ferrite. Three Nb microalloyed steels were thermomechanically processed in the laboratory and coiled at different temperatures to investigate the effect of Nb content on the tensile properties. The extra strength was linearly related to the Nb remaining in solution after the hot working. The maximum contribution from Nb was reached for a coiling temperature of 873?K (600?°C).