Finite elements/Taguchi method based procedure for the identification of the geometrical parameters significantly affecting the biomechanical behavior of a lumbar disc

The aim of this work is to show a quick and simple procedure able to identify the geometrical parameters of the intervertebral disc that strongly affect the behavior of the FEM model. First, we allocated a selection criterion for the minimum number of geometrical parameters that describe, with a good degree of approximation, a healthy human vertebra. Next, we carried out a sensitivity analysis using the ‘Taguchi orthogonal array’ to arrive at a quick identification of the parameters that strongly affect the behavior of the Fem model.     

Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi’s [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450’s 2C9 and 2C19. Lowering the log D by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.     

On the PBB Designs for Multiresponse Experiments

We present the idea of using multiresponse incomplete block designs when not all responses can be observed in all experimental units. For a special class of such designs, in which partial designs are PBB designs, a method for estimating natural treatment contrast is given. We also consider the problem of testing the hypotheses concerning the natural and any estimable treatment contrasts. For testing this hypothesis the Wald statistics, being asymptotically chi-square distributed, is proposed.     

On Connectedness of a Two-way Elimination of Heterogeneity Design

For some subclass of a two-way elimination of heterogeneity design, necessary and sufficient conditions are established for row-connectedness and column-connectedness of a design to imply its connectedness.     

Design and Analysis of Field Experiments Incorporating Local and Remote Effects of Treatments

Design and analysis of field experiments in the presence of local and remote treatment effects are considered. The design criteria are optimality and balance for estimating local and remote effects. A nonlinear model, where remote effects are assumed to be proportional to the local effects, has been discussed.     

Contingent valuation and biodiversity: measuring the user surplus of Kenyan protected areas

The financial returns to Kenyan tourism demonstrate the importance of the country's tourist potential to its economic development. Protected areas and their inhabitants are the principal focus of the tourist industry, the nations's main foreign exchange earner, and a source of wonder and value for a global population of non-users. It might be expected that such assets would be accorded some degree of security with sufficient funding to safeguard current and potential economic benefits. Yet park use is haphazard, and there is frequently little coincidence between those that benefit and those that pay for the continued existence of such areas. Growing economic and demographic pressures which threaten to swamp protected areas only emphasize the implicit subsidy currently paid by Kenyans to support conservation for the benefit of the world at large. In this climate the case for conservation depends on the measurement and capture of economic benefits. Using a contingent valuation survey of expressed preference this study estimates the consumer surplus attached to current non-consumptive use of protected areas by foreign visitors at some $450 million per annum. This sum alone is more than double the best available estimate of opportunity cost and appears to justify current resource use. The estimate is additional to current financial returns from tourism and makes no allowance for other direct and indirect benefits and potential returns from consumptive uses. Measured consumer surplus contains some margin of willingness to pay that could be captured through the current fee structure. Moreover, park fees represent the most accessible market mechanism to finance revenue sharing and additional park investment before potential recourse to emerging global market institutions.     

Recent Advances in the use of Immobilized Lipases Directed Toward the Asymmetric Syntheses of Complex Molecules

Water-insoluble compounds can be substrates for enzymatic reactions when lipases are immobilized properly and suitable organic solvents are used. In this review, three type of lipase immobilization method and their application to the asymmetric syntheses of complex molecules are described. Lipases immobilized with Celite or synthetic prepolymers such as urethane prepolymer and photo-crosslinkable resin prepolymer have been applied for the kinetic resolution of many kinds of water-insoluble substrate.

Phospholipid-lipase aggregates with ether linkages are novel and have been found to function effectively as immobilized lipases in asymmetric hydrolysis or esterification reactions in water-saturated organic solvent. The phospholipid-lipase aggregates are considered to have a stacked bilayer based on X-ray diffraction analysis structure of the lipid in the crystalline phase.     

Sampling Atriplex bladders: a comparison of methods

Abstract. A major objection to the convenient sampling of Chenopodiacean bladders by brushing in aqueous solutions is the suspected leakage of ions from the leaf blade. To overcome this problem, a new method of sampling bladder hair is described, which also achieves rapid and quantitative separation and, at the same time, yields bladder samples of undoubtedly high purity. Leakage is stopped by the aid of liquid nitrogen. Comparison of this method to removal of bladders by brushing in aquenous solutions effectively confirm the validity of the customary method beyond dispute.