Rationally designed inhibitors as tools for comparing the mechanism of squalene-hopene cyclase with oxidosqualene cyclase

The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of bacterial membranes catalyzing the formation of pentacyclic sterol-like triterpenes, was studied by using different classes of compounds originally developed as inhibitors of oxidosqualene cyclase (OCS) (E.C. 5.4.99.7), the enzyme of eukaryotes responsible for the formation of tetracyclic precursors of sterols. The mechanism of cyclization of squalene by SHC, beginning with a protonation of the 2,3 double bond by an acidic residue of the enzyme, followed by a series of electrophilic additions of the carbocationic intermediates to the double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by OSC. The inhibitors studied included: (i) analogs of the carbocationic intermediates formed during cyclization, such as aza-analogs of squalene and 2,3-oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the substrates. Comparison of the results obtained with the two enzymes, SHC and OSC, showed that many of the most effective inhibitors of OSC were also able to inhibit SHC, while some derivatives acted as specific inhibitors. Differences could be easily explained on the basis of the different substrate specificity of the two enzymes.     

Synthesis and catalytic activity of optically active polymers containing oxime groups

Optically active polymers containing oxime groups have been prepared: (i) by partial quaternization of poly(4-vinyl pyridine) (P4VP) with phenacyloxime bromide and with (+)-(S)-1-bromo-2-methylbutane; and (ii) by reaction of the copolymer from 4VP and (+)-(S)-5-methyl-1-hepten-3-one with hydroxylamine. These polymers have been used as catalysts for the esterolysis of esters of p-nitrophenol with non-chiral and with chiral acids. The kinetic parameters of the catalytic process are markedly dependent on the structure of polymer and substrate. A moderate chiral discrimination of the antipodes of p-nitrophenyl 2-methylbutanoate is observed with the catalyst obtained from the copolymer of 4VP with (+)-(S)-5-methyl-1-hepten-3-one.     

How the risk of failure in lifetime of tempered glass depends on the size of NiS inclusions and heat soak test duration

The probability of breakage in service lifetime of heat-tempered glass panes contaminated by nickel sulfide inclusions is estimated with a multiscale micromechanically motivated statistical theory, which considers the effects of the heat soak test (HST). Short and long HSTs differently affect the phase transformation of NiS of diverse chemical composition, whose increase in volume can break the glass. The main hypothesis, corroborated by experiments, is that there is a lower limit for the size of NiS stones below which no crack can be initiated from the volumetric expansion. The catastrophic propagation of nucleated fractures in the long term is modeled through a rescaled critical stress intensity factor, which accounts for the subcritical crack propagation and the slow phase transformation of NiS. A parametric analysis evidences how the failure probability is strongly affected by these parameters, depending on the holding time in the HST. Tailored experimental activity is suggested for the proper calibration of the model.     

Dipyridamole technetium-99m Sestamibi imaging in the diagnosis of syndrome X

In a middle-aged woman with anginal chest pain and a normal-appearing angiogram, dypiridamole technetium-99m Sestamibi scintigraphy, a noninvasive method, provided the diagnosis of syndrome X and was used in follow-up to monitor the course of disease.     

Sensitivity analysis of the rice model WARM in Europe: Exploring the effects of different locations,climates and methods of analysis on model sensitivity to crop parameters

Sensitivity analysis studies how the variation in model outputs can be due to different sources of variation. This issue is addressed, in this study, as an application of sensitivity analysis techniques to a crop model in the Mediterranean region. In particular, an application of Morris and Sobol' sensitivity analysis methods to the rice model WARM is presented. The output considered is aboveground biomass at maturity, simulated at five rice districts of different countries (France, Greece, Italy, Portugal, and Spain) for years characterized by low, intermediate, and high continentality. The total effect index of Sobol' (that accounts for the total contribution to the output variation due a given parameter) and two Morris indices (mean μ and standard deviation σ of the ratios output changes/parameter variations) were used as sensitivity metrics. Radiation use efficiency (RUE), optimum temperature (T_opt), and leaf area index at emergence (LAI_ini) ranked in most of the combinations site × year as first, second and third most relevant parameters. Exceptions were observed, depending on the sensitivity method (e.g. LAI_ini resulted not relevant by the Morris method), or site-continentality pattern (e.g. with intermediate continentality in Spain, LAI_ini and T_opt were second and third ranked; with low continentality in Portugal, RUE was outranked by T_opt). Low σ values associated with the most relevant parameters indicated limited parameter interactions. The importance of sensitivity analyses by exploring site × climate combinations is discussed as pre-requisite to evaluate either novel crop-modelling approaches or the application of known modelling solutions to conditions not explored previously. The need of developing tools for sensitivity analysis within the modelling environment is also emphasized.     

Analysis of Nodular Cast Iron Microstructures for Micromechanical Model Development

Abstract:  One of the main factors in determining the different grades of ductile iron is the matrix structure. In the as-cast condition, the matrix will consist of varying proportions of pearlite and ferrite, and as the amount of pearlite increases, the strength and hardness of the iron also increase. Three different nodular cast irons are here considered and their microstructure characterised in detail using metallographic methods. Then micromechanics models based on the unit cell approach and the finite element method are introduced to describe the actual constitutive response of the materials and the predicted behaviours are compared with experiments.     

Optimal controllers for spatially invariant systems with delayed communication requirements

We consider the problem of optimal design of semi-decentralized controllers for a special class of spatially distributed systems. This class includes spatially invariant and distributed discrete-time systems with an inherent temporal delay in the interaction of neighboring sites. We consider the problem of optimal design of distributed controllers that have the same information passing delay structure as the plant. We show how for stable plants, the YJBK parameterization of such stabilizing controllers yields a convex parameterization for this class. We then show how the optimal problem can be solved.     

Interplay between upsampling and regularization for provider fairness in recommender systems

User Modeling and User-Adapted Interaction - Considering the impact of recommendations on item providers is one of the duties of multi-sided recommender systems. Item providers are key stakeholders...     

Double Mutant Cycles as a Tool to Address Folding,Binding, and Allostery

Quantitative measurement of intramolecular and intermolecular interactions in protein structure is an elusive task, not easy to address experimentally. The phenomenon denoted ‘energetic coupling’ describes short- and long-range interactions between two residues in a protein system. A powerful method to identify and quantitatively characterize long-range interactions and allosteric networks in proteins or protein–ligand complexes is called double-mutant cycles analysis. In this review we describe the thermodynamic principles and basic equations that underlie the double mutant cycle methodology, its fields of application and latest employments, and caveats and pitfalls that the experimentalists must consider. In particular, we show how double mutant cycles can be a powerful tool to investigate allosteric mechanisms in protein binding reactions as well as elusive states in protein folding pathways.