Supporting the identification of novel fragment-based positive allosteric modulators using a supervised molecular dynamics approach: A retrospective analysis considering the human A2A adenosine receptor as a key example

Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal and collaborators reported an interesting study, performed on a detergent-solubilized StaR adenosine A2A receptor, describing the existence of both fragment-like negative allosteric modulators (NAMs), and fragment-like positive allosteric modulators (PAMs). From this retrospective study, our results suggest that Supervised Molecular Dynamics (SuMD) simulations can support, on a reasonable time scale, the identification of fragment-like PAMs following their receptor recognition pathways and characterizing the possible allosteric binding sites

Mechanism of wave breaking from a vacuum point in the defocusing nonlinear Schrödinger equation

We study the wave breaking mechanism for the weakly dispersive defocusing nonlinear Schrödinger equation with a constant phase dark initial datum that contains a vacuum point at the origin. We prove by means of the exact solution to the initial value problem that, in the dispersionless limit, the vacuum point is preserved by the dynamics until breaking occurs at a finite critical time. In particular, both Riemann invariants experience a simultaneous breaking at the origin. Although the initial vacuum point is no longer preserved in the presence of a finite dispersion, the critical behavior manifests itself through an abrupt transition occurring around the breaking time

Magnetic pattern at supergranulation scale: the Void Size Distribution

The large-scale magnetic pattern of the quiet sun is dominated by the magnetic network. This network, created by photospheric magnetic fields swept into convective downflows, delineates the boundaries of large scale cells of overturning plasma and exhibits voids in magnetic organization. Such voids include internetwork fields, a mixed-polarity sparse field that populate the inner part of network cells. To single out voids and to quantify their intrinsic pattern a fast circle packing based algorithm is applied to 511 SOHO/MDI high resolution magnetograms acquired during the outstanding solar activity minimum between 23 and 24 cycles. The computed Void Distribution Function shows a quasi-exponential decay behavior in the range 10-60 Mm. The lack of distinct flow scales in such a range corroborates the hypothesis of multi-scale motion flows at the solar surface. In addition to the quasi-exponential decay we have found that the voids reveal departure from a simple exponential decay around 35 Mm.Comment: 6 pages, 8 figures, to appear in Astronomy and Astrophysic

Consumer's Attitude Towards Labeled and Unlabeled GM Food Products in Italy

Based on survey data collected on a sample of 500 Italian consumers, this paper evaluates the consumer's attitude towards foods obtained from the application of biotechnologies and foods labeled as "GM free". Results from the application of probit models shows that the probability to purchase GM products is lower for individuals more adverse to risk, older, with higher education and less confident in institutional guarantees. Willingness to Pay for GM free products is positively related to information, risk aversion, age, trust in institutional environment, negatively to the degree of agreement with the application of biotechnologies.Food Consumption/Nutrition/Food Safety, Research and Development/Tech Change/Emerging Technologies,

Elastographic presentation of medullary thyroid carcinoma

Aim of the study was to evaluate the elastographic appearance of medullary thyroid carcinoma (MTC) by a retrospective evaluation of 18 nodules histologically proven as MTC. Free-hand qualitative elastography was performed using Hitachi Logos EUB 7500. The elasticity score (ES), was assessed based on a colour elastogram, the blue colour being correlated with hard tissue, red colour with soft tissue, and green with intermediate hardness. Nodules were classified into four classes. A alleged diagnosis of malignancy was assigned to nodules with ES3 or 4 and a presumptive diagnosis of benignity was assigned to nodules with an ES1 or 2. More than half (55.6 %) of MTCs have a low-intermediate grade of elasticity. The hardest lesions (ES4) were those with ultrasonographic features highly suspicious for malignancy. In conclusion, most of MTCs present an elastographic pattern of benignity. Therefore, qualitative elastography does not add useful information in pointing out MTC on the basis of its hardness. Our data suggest a marginal role for this technique in MTC evaluation

Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: An overview

Computational techniques have been applied in the drug discovery pipeline since the 1980s. Given the low computational resources of the time, the first molecular modeling strategies relied on a rigid view of the ligand-target binding process. During the years, the evolution of hardware technologies has gradually allowed simulating the dynamic nature of the binding event. In this work, we present an overview of the evolution of structure-based drug discovery techniques in the study of ligand-target recognition phenomenon, going from the static molecular docking toward enhanced molecular dynamics strategies

Guida alla flora delle Alpi Carniche meridionali (Ampezzo - Sauris)

This book is a guide to the vascular plants occurring in the sector of the southern Carnic Alps (NE Italy) that stretches from Ampezzo to Sauris (Province of Udine), plus the adjoining area in the Province of Belluno which includes M. Bivera, M. Tiarfin and the subalpine meadows around Casera Razzo (1244 infrageneric taxa). The general introduction is followed by an original dichotomous key produced using software FRIDA, illustrated by photographs and ecological-biogeographical notes for all species. The appendix contains some elementary notions of Botany and an index of the scientific names associated with those of the respective families.Il volume è una guida alle piante vascolari sinora note per il settore delle Alpi Carniche meridionali che si estende da Ampezzo alla Conca di Sauris (UD), comprendendo anche un’area in provincia di Belluno che include il M. Bivera, il M. Tiarfin e i pascoli subalpini nei dintorni di Casera Razzo (1244 tra specie e sottospecie). L’introduzione generale è seguita da una chiave dicotomica originale, prodotta utilizzando il programma FRIDA, illustrata da fotografie e note ecologico-biogeografiche per tutte le specie. L’appendice contiene alcune nozioni di botanica elementare e l’indice dei nomi scientifici delle piante associati a quelli delle rispettive famiglie

A Supervised Molecular Dynamics Approach to Unbiased Ligand–Protein Unbinding

The recent paradigm shift toward the use of the kinetics parameters in place of thermodynamic constants is leading the computational chemistry community to develop methods for studying the mechanisms of drug binding and unbinding. From this standpoint, molecular dynamics (MD) plays an important role in delivering insight at the molecular scale. However, a known limitation of MD is that the time scales are usually far from those involved in ligand–receptor unbinding events. Here, we show that the algorithm behind supervised MD (SuMD) can simulate the dissociation mechanism of druglike small molecules while avoiding the input of any energy bias to facilitate the transition. SuMD was tested on seven different intermolecular complexes, covering four G protein-coupled receptors: the A2A and A1 adenosine receptors, the orexin 2 and the muscarinic 2 receptors, and the soluble globular enzyme epoxide hydrolase. SuMD well-described the multistep nature of ligand–receptor dissociation, rationalized previous experimental data and produced valuable working hypotheses for structure–kinetics relationships

I licheni epifiti del Parco Naturale di Paneveggio-Pale di San Martino

Da molti anni, nel Parco di Paneveggio-Pale di San Martino sono in corso ricerche sui licheni che hanno permesso di realizzare un inventario delle specie e di apportare contributi originali alle conoscenze sulla loro ecologia. Il Parco di Paneveggio ha una missione molto importante nella conservazione dei licheni: nel suo territorio ne sono noti quasi 650, pari al 50% dei licheni del Trentino-Alto Adige, che è la regione italiana con il maggior numero di specie note. Tuttavia, una stima realistica della biodiversità lichenica del Parco potrebbe essere di circa 900 specie! Il Parco ha commissionato al Dipartimento di Scienze della Vita dell'Università di Trieste la realizzazione di una guida interattiva ai licheni epifiti, che al momento include 242 specie e che è consultabile in rete dal sito del Parco o da quello del progetto Dryades (www.dryades.eu). L'identificazione dei macrolicheni (licheni fruticosi, fogliosi e squamulosi) può essere effettuata anche senza l'uso del microscopio,ed è quindi più facile. Al contrario, per l'identificazione dei licheni crostosi è spesso indispensabile osservare caratteri anatomici al microscopio, soprattuto quelli relativi alle spore