Conformational analysis of aliskiren, a potent renin inhibitor, using high-resolution nuclear magnetic resonance and molecular dynamics simulations

Aliskiren is a nonpeptide antihypertensive drug that potently inhibits the human enzyme renin in vitro and in vivo. Many clinical trials have shown the efficacy of aliskiren to lower blood pressure in correlation with other antihypertensive agents. In this report, the conformational behavior of aliskiren is studied in water, trifluoroethanol, and dimethylformamide solutions by means of 2D-NMR spectroscopy and molecular dynamics simulations. The stereochemical characteristics of aliskiren in different solutions, in combination with the previously published crystal structure of the renin-aliskiren complex have been investigated. The aim of this study was to explore the conformational behavior of this first successful renin inhibitor in relation to its environment. In aqueous solution, aliskiren adapts a U-shape conformation, whereas in DMF, the molecule is basically endowed with an "extended" conformation, which has more similarities to the one bound to the receptor.     

Which, if any, hydrates will crystallise? Predicting hydrate formation of two dihydroxybenzoic acids

A study of two dihydroxybenzoic acid isomers shows that computational methods can be used to predict hydrate formation, the compound:water ratio and hydrate crystal structures. The calculations also help identify a novel hydrate found in the solid form screening that validates this study.     

TiO2-ZrO2 affinity chromatography polymeric microchip for phosphopeptide enrichment and separation

We fabricated a TiO(2)-ZrO(2) affinity chromatography micro-column on 2 mm PMMA plates, and demonstrated the enrichment and separation of (a) a standard mono- and tetra-phosphopeptide, and (b) phosphopeptides contained in a tryptic digest of β-Casein. The chromatography column consisted of 32 parallel microchannels with common input and output ports and was fabricated by lithography directly on the polymeric substrate followed by plasma etching (i.e. standard MEMS processing) and sealed with lamination. The liquid deposited TiO(2)-ZrO(2) stationary phase was characterized by X-ray diffraction and was found to be mostly TiO(2) and ZrO(2) in crystalline phases. Off-chip UV detection and MALDI MS identification of the separated effluents were used. The chip had a capacity of >1.4 μg (0.7 nmol) of a prototype mono-phosphopeptide and a recovery of 94 ± 3%, and can be used with small samples (less than 0.1 μL depending on the syringe pump used). The chip design allows an expansion of its capacity by means of increasing the number of parallel microchannels at a constant sample volume. Our approach provided an alternative to off-line extraction tips (with typical capacities of 1-2 μg and sample volumes of 1-10 μL), and to on-chip efforts based on packed bed and frit formats.     

Numerical exploration of Kaldorian interregional macrodynamics: stability and the trade threshold for business cycles under fixed exchange rates

The stability of equilibrium and the possibility of generation of business cycles in a discrete interregional Kaldorian macrodynamic model with fixed exchange rates are explored using numerical methods. One of the aims is to illustrate the feasibility and effectiveness of the numerical approach for dynamical systems of moderately high dimensionality and several parameters. The model considered is five-dimensional with four parameters, the speeds of adjustment of the goods markets and the degrees of economic interactions between the regions through trade and capital movement. Using a grid search method for the determination of the region of stability of equilibrium in two-dimensional parameter subspaces, and coefficient criteria for the flip bifurcation - and Hopf bifurcation - curve, we determine the stability region in several parameter ranges and identify Hopf bifurcation curves when they exist. It is found that interregional cycles emerge only for sufficient interregional trade. The relevant threshold is predicted by the model at 14 - 16 % of trade transactions. By contrast, no minimum level of capital mobility exists in a global sense as a requirement for the emergence of interregional cycles; the main conclusion being, therefore, that cycles may occur for very low levels of capital mobility if trade is sufficient. Examples of bifurcation and Lyapunov exponent diagrams illustrating the occurrence of cycles or period doubling, and examples of the development of the occurring cycles, are given. Both supercritical and subcritical bifurcations are found to occur, the latter type indicating coexistence of a point and a cyclical attractor.     

A homogenization approach to flashing ratchets

The paper continues the program of the authors to develop a mathematical framework to understand and characterize the notion of “asymmetric” potentials, which has been introduced to explain how molecular motors work, considering flashing ratchets, i.e., molecules diffusing in a potential with periodic switches. The mathematical model is a Fokker–Planck equation with a space–time periodic potential and diffusion of order of magnitude compatible with the period of the potential. After performing a homogenization analysis of the problem the “asymmetric” potentials are characterized by the property that the solution, which models the molecule density, concentrates on one end of the domain. Finally explicit examples are presented exhibiting that the concentration phenomena (motor effect) takes place are presented. The proof uses techniques from the theory of viscosity solutions for the Hamilton–Jacobi equation which, in the homogenization limit, defines the effective hamiltonian.     

Bayesian statistical process control for Phase I count type data

Count data, most often modeled by a Poisson distribution, are common in statistical process control. They are traditionally monitored by frequentist c or u charts, by cumulative sum and by exponentially weighted moving average charts. These charts all assume that the in‐control true mean is known, a common fiction that is addressed by gathering a large Phase I sample and using it to estimate the mean. “Self‐starting” proposals that ameliorate the need for a large Phase I sample have also appeared. All these methods are frequentist, ie, they allow only retrospective inference during Phase I, and they have no coherent way to incorporate less‐than‐perfect prior information about the in‐control mean. In this paper, we introduce a Bayesian procedure that can incorporate prior information, allow online inference, and should be particularly attractive for short‐run settings where large Phase I calibration exercises are impossible or unreasonable.     

The renormalization constants of QED in unitary approximation

A unitary approximation for the time-evolution operator given through the exponential representation is used to calculate the renormalization constants of QED. The results obtained by this method are the same as the renormalization group improvement of the usual perturbation series taking into account terms up to the second order ine.     

Simulated annealing and tabu search approaches to unidirectional flowpath design for Automated Guided Vehicle Systems

In this paper, we address the flowpath design issue of Automated Guided Vehicle Systems (AGVSs). In particular, we concentrate on the design of unidirectional flowpaths (i.e. vehicles are restricted to travel only in one direction along a given segment of the flowpath). We have developed intelligent heuristics — simulated annealing and tabu search algorithms for the design of unidirectional AGVSs. Different versions of simulated annealing and tabu search algorithms are implemented. Our extensive computational results indicate that both simulated annealing and tabu search yield solutions of adequate quality for all practical purposes. A tabu search implementation with the use of a frequency-based memory structure dominates all tested heuristics in terms of solution quality (i.e. percent deviation from optimality), with an impressive average performance over 45 test problems of less than 0.85% deviation from optimality.