N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT₂-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT₁ and MT₂ binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.     

Analysis of the Electromagnetic Interaction Between a Resonator and a Lossy Dielectric Body as a First Theoretical Approach to Noninvasive Heart Movement Detection

In this paper the electromagnetic interaction between a resonator and a lossy dielectric body is examined by means of a simple model suitable for computer simulation; the body was assumed to have a revolution form and the resonator was electromagnetic coupled to the body by its inductive element constituted by a planar circular or spiral coil. On the basis of the model a computer program was derived which allows a simple numerical evaluation of the variation in the resonant frequency caused by the interaction mentioned above.     

Rapid and Simultaneous Analysis of Xanthines and Polyphenols as Bitter Taste Markers in Bakery Products by FT-NIR Spectroscopy

The food industry has a direct interest into bitter-tasting substances either for the identification of negative off-flavors or for the monitoring of a desired organoleptic quality. A rapid technique, based on Fourier transform-near infrared (FT-NIR) spectroscopy and able to detect taste molecular markers in bakery commodities, was developed, focusing the attention on biscuits category. Xanthines (caffeine, theobromine, and theophylline) and polyphenols (catechins and epicathechins), considered as mainly responsible for the bitter-taste of coffee\cocoa\chocolate based products, were firstly checked using a confirmatory liquid chromatography (LC)-ESI\mass spectrometry (MS)-MS procedure after hot methanol–water extraction. Correspondent data were used for the calibration of the FT-NIR through PLS regression. Values of the standard errors of prediction (lower than 10 %) were comparable to the values of the standard errors of cross-validation. Coefficients of determination indicated a good predictive power in the calibration model (R ² xanthines?=?0.97, R ² polyphenols?=?0.96) and a satisfying discriminating power among different contents in the validation models (R ² xanthines?=?0.96, R ² polyphenols?=?0.96). A testing phase on the generated model was executed by a comparison of LC-MS and sensory panel data with FT-NIR responses recorded on unknown biscuits: differences between found and predicted levels were generally below 5 % and the best predictability was achievable in chocolate-based biscuits. This methodology is able to work directly on solid products, has the potential to be expanded on other categories of gustative molecular markers (like sugars) and can be conceived as applicable for a routine control of a standardized bitter taste quality in a real industrial production.     

Mechanical Defects Deriving from the Manufacturing Process of High-Density Electronic Boards: Experimental Analysis of Critical Factors

Current market demand calls for electronic boards that are increasingly sophisticated, of high technological content, with high standards of quality and reliability, and cost as low as possible. The high-density electronic boards produced for applications in the biomedical, aerospace, telecommunications, and automation industries are designed using sophisticated procedures that yield optimum results with regard to electronic performances. However, the physical/mechanical and thermal aspects involved in the practical realization of the boards are still based on technological processes that are not as well controlled or as well known with regard to sensitivity to the various characteristic parameters. This results in a high rate of defects occurring in the case of particularly critical boards, due to which finished boards are frequently rejected at inspection or even in service, with significant financial loss. A study has been conducted focusing on qualitative and quantitative analysis of the deformation, and on twisting deformation in particular, of semifinished products during the manufacturing process. A specific procedure has been developed for making measurements and acquiring experimental data, in a research activity commissioned by an Italian company which manufactures electronic boards. Processing of the data and subsequent analysis of the results has made it possible to analyze the production stages having the greatest influence of the extent of the final deformation.     

MT1‐Selective Melatonin Receptor Ligands: Synthesis,Pharmacological Evaluation,and Molecular Dynamics Investigation of N‐{[(3‐O‐Substituted)anilino]alkyl}amides

The design of compounds selective for the MT₁ melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT₁ subtype, and only few selective compounds have been reported so far. N‐(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT₁/MT₂ agonists and MT₂‐selective antagonists. We synthesized a new series of N‐(anilinoalkyl)amides bearing 3‐arylalkyloxy or 3‐alkyloxy substituents at the aniline ring, looking for new potent and MT₁‐selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a , which was endowed with high MT₁ binding affinity (pK_i=8.93) and 78‐fold selectivity for the MT₁ receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3‐arylalkyloxy substituent, we built a homology model of the MT₁ receptor based on the β₂ adrenergic receptor crystal structure in its activated state. A binding mode for MT₁ agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT₁ selectivity of compounds with lipophilic arylalkyloxy substituents.     

The inverse type II β-turn on D-Trp-Phe, a pharmacophoric motif for MOR agonists

Herein we propose the D ‐Trp‐Phe sequence within an inverse type II β‐turn as a new kind of pharmacophoric motif for μ‐opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr‐D ‐Pro‐D ‐Trp‐Phe‐Gly] ( 4 ), an analogue of endomorphin‐1 (H‐Tyr‐Pro‐Trp‐Phe‐NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10^?8 M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D ‐Trp‐Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β‐turn. These efforts led to c[Tyr‐Gly‐D ‐Trp‐Phe‐Gly] ( 14 ) and to the cyclotetrapeptide c[D ‐Asp‐1‐amide‐β‐Ala‐D ‐Trp‐Phe] ( 15 ), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ‐ and δ‐opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β‐turn in binding. These results indicate that the D ‐Trp‐Phe inverse β‐turn structure can be used for designing non‐endomorphin‐like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.     

Digital image analysis to enhance underwritten text in the Archimedes palimpsest

This paper reports some of the results obtained by applying statistical processing techniques to multispectral images of the Archimedes palimpsest. We focused on the possibilities of extracting the faint and highly degraded underwritten text, which constitutes the most ancient source for several treatises by Archimedes. Assuming each image to be generated by a linear mixture of different patterns, characterized by different emissivity spectra, the specific difficulty in separating the underwriting is that the mixture coefficients are unknown. To solve this problem, we rely on statistical techniques that maximize the information content of the processed images. In particular, we assessed the performances of the principal component analysis (PCA) and the independent component analysis (ICA) techniques. On the basis of 14 hyperspectral views of part of the palimpsest, we succeeded to extract clean maps of the primary Archimedes text, the overwritten text, and the mold pattern present in the pages. This goal was not reached in all the cases, because of the non-perfect adherence of the data model to reality. In most cases, however, PCA and ICA produced a significant enhancement of the underwritten text. This work has been supported by the European Commission project “Isyreadet” (http://www.isyreadet.net), under contract IST-1999-57462. Partial support from the European Network of Excellence MUSCLE (http://www.muscle-noe.org), FP6-507752, is also acknowledged.     

Study of serum alanine-aminotransferase levels in blood donors in Spain

BACKGROUND AND OBJECTIVE: Serum alanine-aminotransferase (ALT) is being used as a surrogate test for preventing post-transfusion viral hepatitis. However, ALT elevation is influenced by many factors. We have studied ALT levels in 1,036 consecutive blood donors to determine their association with gender, obesity, and hepatitis virus infection markers. DESIGN AND METHODS: In each donation aspartate-aminotransferase (AST), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (gamma GT) activity were also determined and body mass index (BMI) was calculated. RESULTS: Five hundred seventy-nine men and 457 women donated blood; ALT activity was 25.3 +/- 14.5 IU/L (mean +/- SD) for men and 16.3 +/- 7.9 IU/L for women (p < or = 0.0005). The upper normal value for men was 56 IU/L and 34 IU/L for women. On applying this value to the study group 4.8% of the men and 2% of the women had values greater than the cutoff. Among the men with increased ALT levels, 53.5% had a BMI > 27, 7.1% also had an increased level of GGT and 7.1% had increased levels of AST and LDH. None of them were HBsAg nor anti-HCV positive. Among the women with increased ALT, 33.3% had BMI > 27, 33.3% had increased levels of LDH and AST, and 11.1% were anti-HCV positive (only 1 donor). INTERPRETATION AND CONCLUSIONS: It seems clear that different cutoff values should be considered for men and women. Factors such as obesity, may account for more than 50% of the cases with increased ALT values, indicating the low specificity of the test.