Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH4R Antagonism

The human histamine H₄ receptor (hH₄R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH₄R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH₄R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH₄R bioactivity. An application of the prediction model on external test set composed of more than 160 hH₄R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼4000 chemicals highly indexed as H₄R antagonists'' candidates. Next, a series of 3D models of hH₄R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH₄R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner.     

Breeding system of diploid sexuals within the Ranunculus auricomus complex and its role in a geographical parthenogenesis scenario

The larger distribution area of asexuals compared with their sexual relatives in geographical parthenogenesis (GP) scenarios has been widely attributed to the advantages of uniparental reproduction and polyploidy. However, potential disadvantages of sexuals due to their breeding system have received little attention so far. Here, we study the breeding system of five narrowly distributed sexual lineages of Ranunculus notabilis s.l. (R. auricomus complex) and its effects on outcrossing, inbreeding, female fitness, and heterozygosity. We performed selfing and intra‐ and interlineage crossings by bagging 481 flowers (59 garden individuals) followed by germination experiments. We compared seed set and germination rates, and related them to genetic distance and genome‐wide heterozygosity (thousands of RADseq loci). Selfings (2.5%) unveiled a significantly lower seed set compared with intra‐ (69.0%) and interlineage crossings (69.5%). Seed set of intra‐ (65%) compared to interpopulation crossings (78%) was significantly lower. In contrast, all treatments showed comparable germination rates (32%–43%). Generalized linear regressions between seed set and genetic distance revealed positive relationships in general and between lineages, and a negative one within lineages. Seed set was the main decisive factor for female fitness. Germination rates were not related to genetic distance at any level, but were positively associated with heterozygosity in interlineage crossings. Experiments confirmed full crossability and predominant outcrossing among sexual R. notabilis s.l. lineages. However, up to 5% (outliers 15%–31%) of seeds were formed by selfing, probably due to semi‐self‐compatibility in a multi‐locus gametophytic SI system. Less seed set in intrapopulation crossings, and higher seed set and germination rates from crossings of genetically more distant and heterozygous lineages (interlineage) indicate negative inbreeding and positive outbreeding effects. In GP scenarios, sexual species with small and/or isolated populations can suffer from decreased female fitness due to their breeding system. This factor, among others, probably limits range expansion of sexuals.     

8,000 years of climate,vegetation, fire and land-use dynamics in the thermo-mediterranean vegetation belt of northern Sardinia (Italy)

Vegetation History and Archaeobotany - Knowledge about the vegetation history of Sardinia, the second largest island of the Mediterranean, is scanty. Here, we present a new sedimentary record...     

Integration of life cycle assessment into a decision support system for selecting sustainable road asphalt pavement mixtures prepared with waste

The International Journal of Life Cycle Assessment - A challenge that the road paving sector is facing concerns the achievement of highly performing bituminous asphalt mixture solutions that do not...     

A depth-dependent model of the pericellular microenvironment of chondrocytes in articular cartilage

Experimental studies suggest that the magnitude of chondrocyte deformation is much smaller than expected based on the material properties of extracellular matrix (ECM) and cells, and that this result could be explained by a structural unit, the chondron, that is thought to protect chondrocytes from large deformations in situ. We extended an existing numerical model of chondrocyte, ECM and pericellular matrix (PCM) to include depth-dependent structural information. Our results suggest that superficial zone chondrocytes, which lack a pericellular capsule (PC), are relatively stiff, and therefore are protected from excessive deformations, whereas middle and deep zone chondrocytes are softer but are protected by the PC that limits cell deformations in these regions. We conclude that cell deformations sensitively depend on the immediate structural environment of the PCM in a depth-dependent manner, and that the functional stiffness of chondrocytes in situ is much larger than experiments on isolated cells would suggest.     

Osservazioni ecologiche preliminari su Petagnia saniculifolia Guss., raro endemismo siculo

Abstract

Preliminary ecological observations on Petagnia saniculifolia Guss., a rare sicilian endemism. — The Authors present the preliminary results of some observations on the anatomy and ecology of Petagnia saniculifolia Guss. and a synthetic phytosociological table in which some species of Molinio-Arrhenatheretea and Querco-Fagetea are present. The particular needs of this species and the precarious environmental conditions are pointed out.