Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in {"type":"entrez-nucleotide","attrs":{"text":"HS203873","term_id":"313347069"}}HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds.     

Iterative Optimization of an ESI IT Mass Spectrometer Using Regular Simplex and a Multivariate Target Function Representing the S/N Ratio

Standard automatic tuning for mass spectrometry usually exploits a one-variable-at-a-time approach. This method suffers from important drawbacks: the target function selected for optimization improves the signal of a single channel or a pool of channels without considering noise; the interactions between the parameters are not evaluated. The optimization of the experimental settings of an ESI IT mass spectrometer is carried out here by a multivariate procedure exploiting a target function representing the S/N ratio calculated by principal component analysis and a regular simplex optimization algorithm. A preliminary feasibility study was performed since the target function must be sensitive to the changes in the experimental conditions applied during the iterative tuning and be free from drifts. The feasibility study was carried out to evaluate: the presence of memory effects; the size of the variations in the S/N ratio; the number of scans needed to generate a reliable S/N ratio; the concentration of the multi-standard mixture to use during tuning; the experimental duration required to achieve S/N stability when the experimental settings are modified. The feasibility study led to the identification of the best protocol to accomplish the tuning, while simplex optimization allowed the S/N ratio to be improved by about 70% with respect to the default conditions suggested by the manufacturer.     

Biological response of hydrogels embedding gold nanoparticles

A nanocomposite hydrogel based on natural polysaccharides and gold nanoparticles (ACnAu) has been prepared and its biological effects were tested in vitro with both bacteria and eukaryotic cells. Antimicrobial tests showed that AC-nAu gels are effective in killing both gram+ (Staphylococcus aureus) and gram- (Pseudomonas aeruginosa) bacteria. LDH assays pointed at a toxic effect towards eukaryotic cell-lines (HepG2 and MG63), in contrast with the case of silver-based hydrogels; cytofluorimetry studies demonstrated an apoptosis-related mechanism induced by increase of ROS intracellular level which leads to cell death after 24 h of direct contact with AC-nAu gels. In vivo biocompatibility has been evaluated in a rat model, investigating the peri-implant soft tissue reaction after 1 month of implantation. The results show that silver-containing samples induced a fibrotic capsule of the same average thickness of the control sample (devoid of nanoparticles) (～50 μm), while in the case of gold containing materials the fibrotic capsule was thicker (～100 μm), confirming a higher biocompatibility for silver-based samples than for gold-based ones.     

Probabilistic View of Explosion in an Inelastic Kac Model

Let $\{\mu (\cdot ,t):t\ge 0\}$ be the family of probability measures corresponding to the solution of the inelastic Kac model introduced in Pulvirenti and Toscani (J Stat Phys 114:1453–1480, 2004). It has been proved by Gabetta and Regazzini (J Stat Phys 147:1007–1019, 2012) that the solution converges weakly to equilibrium if and only if a suitable symmetrized form of the initial data belongs to the standard domain of attraction of a specific stable law. In the present paper it is shown that, for initial data which are heavier-tailed than the aforementioned ones, the limiting distribution is improper in the sense that it has probability $1/2$ “adherent” to $-\infty $ and probability $1/2$ “adherent” to $+\infty $ . It is explained in which sense this phenomenon is amenable to a sort of explosion, and the main result consists in an explicit expression of the rate of such an explosion. The presentation of these statements is preceded by a discussion about the necessity of the assumption under which their validity is proved. This gives the chance to make an adjustment to a portion of a proof contained in the above-mentioned paper by Gabetta and Regazzini.     

The First Stable P-Phosphoranyl Substituted Phosphaalkene

Abstract

Interaction of bis(catechoI)chlorophosphorane (1) with two-coordinated phosphorus derivative (2) has been studied by dynamic ³¹P NMR method. The compounds react under soft conditions in methylene chloride with formation of phosphaalkene (5). the first stable representative of Pⁱⁱ-P^v structure derivatives.     

The Features of Organoelement Compounds Conformational Analysis

Abstract

Conformational analysis of organoelement compounds (OEC) has anumber of features. There are some common characteristics of OEC electronic structure to be of importance:     

Microstructural and thermal characterization of neolithic ceramics

The aim of this research was to characterize some Neolithic ceramic finds collected during an excavation carried out at Lugo di Grezzana (Verona, Italy). Pottery shards with different paste and tempers were analyzed to better understand the manufacturing and firing technologies used for their production. Another task of the study was to determine whether highly refined artefacts, found in the site and resembling figulina-type ceramics, were of local production or imported from other places in the north of Italy, where the production of this sort of product has already been unambiguously assessed. Several results emerged from this investigation, providing indications on the finds from this Neolithic settlement and, therefore, on the technological expertise achieved by the primitive community. Moreover, a comparative study carried out on refined ceramic products found in Lugo and genuine figulina items from other northern Italian sites suggests that no trading exchange and commercial routes existed among those primitive communities.     

On the balancing of structural and acoustic performance of a sandwich panel based on topology,property, and size optimization

Balancing structural and acoustic performance of a multi-layered sandwich panel is a formidable undertaking. Frequently the gains achieved in terms of reduced weight, still meeting the structural design requirements, are lost by the changes necessary to regain acceptable acoustic performance. To alleviate this, a design method for a multifunctional load bearing vehicle body panel is proposed which attempts to achieve a balance between structural and acoustic performance. The approach is based on numerical modelling of the structural and acoustic behaviour in a combined topology, size, and property optimization in order to achieve a three dimensional optimal distribution of structural and acoustic foam materials within the bounding surfaces of a sandwich panel. In particular the effects of the coupling between one of the bounding surface face sheets and acoustic foam are examined for its impact on both the structural and acoustic overall performance of the panel. The results suggest a potential in introducing an air gap between the acoustic foam parts and one of the face sheets, provided that the structural design constraints are met without prejudicing the layout of the different foam types.     

Fluid Flow Model for Energy-Aware Server Performance Evaluation

Methodology and Computing in Applied Probability - We use a fluid flow model with reactive bounds to analyze a data processing center with energy-aware servers. The servers switch between four...