A New Potent and Selective Monoamine Oxidase-B Inhibitor with Extended Conjugation in a Chalcone Framework: 1-[4-(Morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one

The general blueprint for the design of monoamine oxidase-B (MAO-B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one (MO10) was prepared by the condensation of 4′-morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC₅₀ value of 0.044 μM along with a selectivity index of 366.13. The IC₅₀ value was better than that of lazabemide (IC₅₀ value of 0.063 μM), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO-B, with a K_i value of 0.0080 μM. The observation of recovery of MAO-B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC₅₀ value of 195.44 μg/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood–brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO-B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.     

Processing-properties relationship of sandwich panels with polypropylene-core and polypropylene-matrix composite skins

This paper reports on the development and the optimization of a thermoforming process (compression molding) for thermoplastic sandwich panels. The skins of the panels are fabricated from polypropylene (PP)/continuous glass fibers dry prepregs in the form of a commingled fabric. The use of two different types of core material has been used, a PP foam and a PP honeycomb. Additionally, two alternative methods for the thermoforming process have been analyzed, using either a one-stage or a two-stage process. In the one-step process, skin molding and skin-core bonding are carried out simultaneously. In the two-stage process, the skins are first thermoformed and then bonded to the core as the second stage. The influence of the selected process parameters on the mechanical properties of the panels has been experimentally investigated, leading to the identification of the preferred processing conditions. Polym. Compos. 25:307–318, 2004. © 2004 Society of Plastics Engineers.     

Zinc(II) Triflate‐Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles

The zinc(II) triflate‐catalyzed synthesis of highly functionalized pyrroles is described. The sequence involves the preliminary preparation of α‐aminohydrazones by Michael addition of primary amines to 1,2‐diaza‐1,3‐dienes. The treatment of these intermediates with dialkyl acetylenedicarboxylates produces α‐(N‐enamino)‐hydrazones that are converted into the corresponding pyrroles. The substituents on the carbon in position four of 1,2‐diaza‐1,3‐dienes drive the regioselectivity of the ring closure process. Starting from 4‐aminocarbonyl‐1,2‐diaza‐1,3‐dienes only dialkyl 1‐substituted 5‐aminocarbonyl‐1H‐pyrrole‐2,3‐dicarboxylates are achieved by Lewis acid‐catalyzed ring closure. A screening of several Lewis/Brønsted acid catalysts is performed. Zinc(II) triflate is the most efficient catalyst. Under similar reaction conditions, employing 4‐alkoxycarbonyl‐1,2‐diaza‐1,3‐dienes, only 4‐hydroxy‐1H‐pyrrole‐2,3‐dicarboxylates are synthesized. These latter reactions can be accomplished regioselectively also in one pot. Using 4‐aminocarbonyl‐1,2‐diaza‐1,3‐dienes, diamines and dialkyl acetylenedicarboxylates the sequence provides the corresponding α,ω‐di(N‐pyrrolyl)alkanes.     

Downexpression of miR-200c-3p Contributes to Achalasia Disease by Targeting the PRKG1 Gene

Achalasia is an esophageal smooth muscle motility disorder with unknown pathogenesis. Taking into account our previous results on the downexpression of miR-200c-3p in tissues of patients with achalasia correlated with an increased expression of PRKG1, SULF1, and SYDE1 genes, our aim was to explore the unknown biological interaction between these genes and human miR-200c-3p and if this relation could unravel their functional role in the etiology of achalasia. To search for putative miR-200c-3p binding sites in the 3′-UTR of PRKG1, SULF1 and SYDE1, a bioinformatics tool was used. To test whether PRKG1, SULF1, and SYDE1 are targeted by miR-200c-3p, a dual-luciferase reporter assay and quantitative PCR on HEK293 and fibroblast cell lines were performed. To explore the biological correlation between PRKG1 and miR-200c-3p, an immunoblot analysis was carried out. The overexpression of miR-200c-3p reduced the luciferase activity in cells transfected with a luciferase reporter containing a fragment of the 3′-UTR regions of PRKG1, SULF1, and SYDE1 which included the miR-200c-3p seed sequence. The deletion of the miR-200c-3p seed sequence from the 3′-UTR fragments abrogated this reduction. A negative correlation between miR-200c-3p and PRKG1, SULF1, and SYDE1 expression levels was observed. Finally, a reduction of the endogenous level of PRKG1 in cells overexpressing miR-200c-3p was detected. Our study provides, for the first time, functional evidence about the PRKG1 gene as a direct target and SULF1 and SYDE1 as potential indirect substrates of miR-200c-3p and suggests the involvement of NO/cGMP/PKG signaling in the pathogenesis of achalasia.     

Selected 1,3-Benzodioxine-Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors

Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones ( CD3, CD8 and CD10 ), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC₅₀ value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC₅₀ value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC₅₀ values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K_i values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.     

Automatic ultrasonic inspection for internal defect detection in composite materials

The detection of internal defects in composite materials with non-destructive techniques is an important requirement both for quality checks during the production phase and in-service inspection during maintenance operations. Visual inspection allows only the analysis of surface characteristics of materials and, then, if internal faults occur inside composite structures, a deeper analysis is required. A comparison between the reactions of different materials to ultrasonic signals can be used to highlight the difference in the internal structures and also to detect the depth position of these anomalies. However, ultrasonic data are difficult to interpret since they require the analysis of a continuous signal for each point of the material under consideration. An automatic procedure is necessary to manage large data sets and to extract significant differences between them.In this paper, we address the problem of automatic inspection of composite materials using an ultrasonic technique. We consider two main steps for interpreting ultrasonic data: the pre-processing technique necessary to normalize the signals of composite structures with different thicknesses and the classification techniques used to compare the ultrasonic signals and detect classes of similar points.     

An SLA-based Broker for Cloud Infrastructures

The breakthrough of Cloud comes from its service oriented perspective where everything, including the infrastructure, is provided “as a service”. This model is really attractive and convenient for both providers and consumers, as a consequence the Cloud paradigm is quickly growing and widely spreading, also in non commercial contexts. In such a scenario, we propose to incorporate some elements of volunteer computing into the Cloud paradigm through the Cloud@Home solution, involving into the mix nodes and devices provided by potentially any owners or administrators, disclosing high computational resources to contributors and also allowing to maximize their utilization. This paper presents and discusses the first step towards Cloud@Home: providing quality of service and service level agreement facilities on top of unreliable, intermittent Cloud providers. Some of the main issues and challenges of Cloud@Home, such as the monitoring, management and brokering of resources according to service level requirements are addressed through the design of a framework core architecture. All the tasks committed to the architecture’s modules and components, as well as the most relevant component interactions, are identified and discussed from both the structural and the behavioural viewpoints. Some encouraging experiments on an early implementation prototype deployed in a real testing environment are also documented in the paper.     

Polyphenol Conjugates and Human Health: A Perspective Review

In recent years, antioxidants have gained great importance because of their potential use in food, pharmaceutical, and cosmetic industries. This interest is rooted in the cumulative evidence connecting active oxygen and free radicals with numerous human degenerative disorders, such as cardiovascular diseases, cancer, aging, and atherosclerosis. Polyphenols are the major class of antioxidant able to reduce the oxidative damages of lipids, proteins, enzymes, carbohydrates, and DNA in living cells and tissues. Among the realm of polyphenol compounds, polyphenol conjugates have been proposed as innovative materials which, by combining the advantageous properties of both the components, can increase the efficiency of antioxidants and their range of application in nutritional and biomedical fields. This work is an overview of the different class of polyphenol conjugates, which will be analyzed in terms of nutritional and biological properties, showing how these bio-conjugates will positively affect the human health.     

Road context evaluated by means of fuzzy interval

In this article, an application of the Hollnagel’s CREAM model, known for its determination of human reliability within complex systems, is proposed and opportunely adapted to road safety and enhanced with a control mechanism of uncertain variables based on the fuzzy interval. The aim of the research is to use an analytical technique that could allow the management in a temporarily and economically convenient way of a great number of variables without losing the information on the uncertainty of the final result. In order to do this, the author has handled the outputs of the fuzzy model with techniques of interval analysis, thus preserving the uncertain content in the following stages of the analysis. The results obtained, expressed with a simple application, permit the determination of the influence that the environmental context exercises towards driver behaviour. Such a model, once in place, allows the rapid examination of further scenarios and in this way is able to constitute an important instrument in the preliminary stages of comparison between other design solutions. Therefore, the methodology is useful not only to quantify the reliability of the route covered by the driver but also to address the strategies of the maintenance towards the improvement of those components of the environmental context that can be critical with regard to road safety.