Linkage isomerism in nitrite reduction by cytochrome cd1 nitrite reductase

Nitrite reduction by cytochrome cd(1) nitrite reductase (cd(1)NIR) is currently accepted to involve coordination of the nitrite nitrogen atom to the ferrous d(1) heme. Here, density functional theory results are reported on the previously unexplored O-binding of nitrite to ferrous and ferric cd(1)NIR. Although the N-isomer (nitro) is energetically favored over the O-nitrite (nitrito), even one single strong hydrogen bond may provide the energy required to put the two isomers on level terms. When hydrogen bonding existent at the cd(1)NIR active site is accounted for in the computational model, the O-nitrite isomer is found to spontaneously protonate and thus yield a ferric-hydroxo species, liberating nitric oxide. An O-nitrite ferrous cd(1)NIR complex appears to be an energetically feasible intermediate for nitrite reduction. O-Coordination would offer an advantage since the end product of nitrite reduction would be a ferric-hydroxo/water complex, rather than the more kinetically inert iron-nitrosyl complex implied by the N-nitrite mechanism.     

Comparison of luminescence ADP production assay and radiometric scintillation proximity assay for Cdc7 kinase

Several assay technologies have been successfully adapted and used in HTS to screen for protein kinase inhibitors; however, emerging comparative analysis studies report very low hit overlap between the different technologies, which challenges the working assumption that hit identification is not dependent on the assay method of choice. To help address this issue, we performed two screens on the cancer target, Cdc7-Dbf4 heterodimeric protein kinase, using a direct assay detection method measuring [(33)P]-phosphate incorporation into the substrate and an indirect method measuring residual ADP production using luminescence. We conducted the two screens under similar conditions, where in one, we measured [(33)P]-phosphate incorporation using scintillation proximity assay (SPA), and in the other, we detected luminescence signal of the ATP-dependent luciferase after regenerating ATP from residual ADP (LUM). Surprisingly, little or no correlation were observed between the positives identified by the two methods; at a threshold of 30% inhibition, 25 positives were identified in the LUM screen whereas the SPA screen only identified two positives, Tannic acid and Gentian violet, with Tannic acid being common to both. We tested 20 out of the 25 positive compounds in secondary confirmatory study and confirmed 12 compounds including Tannic acid as Cdc7-Dbf4 kinase inhibitors. Gentian violet, which was only positive in the SPA screen, inhibited luminescence detection and categorized as a false positive. This report demonstrates the strong impact in detection format on the success of a screening campaign and the importance of carefully designed confirmatory assays to eliminate those compounds that target the detection part of the assay.     

New Method for Theoretical Spinodals Corresponding to Ternary Solutions with an Amphiphile Component

A new method is presented to obtain a theoretical spinodal for ternary solutions with an amphiphile component. This method uses a generalized Wheeler-Widom model representing the ternary solution, and considers local fitting conditions with the experimental binodal, imposing that the theoretical binodal must pass through a point on the experimental binodal, and also that the slope of the theoretical binodal has to be as close as possible to the slope of the representative experimental binodal. Using the previously specified fitting conditions, the corresponding spinodal is derived. The results are in agreement with an older method of local fitting between the generalized Wheeler-Widom model and the experimental data, where the fitting condition implied the coincidence of the theoretical tie-line with the experimental tie-line.     

Decomposing total IR spectra of aqueous systems into solute and solvent contributions: a computational approach using maximally localized Wannier orbitals

The theoretical principles underpinning the calculation of infrared spectra for condensed-phase systems in the context of ab initio molecular dynamics have been recently developed in literature. At present, most ab initio molecular dynamics calculations are restricted to relatively small systems and short simulation times. In this paper we devise a method that allows well-converged results for infrared spectra from ab initio molecular dynamics simulations using small systems and short trajectories characteristic of simulations typically performed in practice. We demonstrate the utility of our approach by computing the imaginary part of the dielectric constant epsilon"(omega) for H2O and D2O in solid and liquid phases and show that it compares well with experimental data. We further demonstrate that maximally localized Wannier orbitals can be used to separate the individual contributions of different molecular species to the linear spectrum of complex systems. The new spectral decomposition method is shown to be useful in present-day ab initio molecular dynamics calculations to compute the magnitude of the "continuous absorption" generated by excess protons in aqueous solutions with good accuracy even when other species present in the solutions absorb strongly in the same frequency window.     

A Bound of the Finslerian Ricci Scalar

In the Riemannian as well as in the Finslerian geometry, certain conditions on the Ricci scalar or the Ricci tensor provide obstructions on the topology of the base manifold and so on the configuration of cut points by limitations of the injectivity radius, see the Bonnet–Myers theorem and its variants and generalizations. In this paper, we show that conversely, prescribing the injectivity radius of a Finsler manifold, some limitations of the Ricci scalar are obtained. Some consequences of the condition that the Ricci tensor is h-parallel with respect to the Chern–Rund connection are found. In addition, some classes of examples are provided.     

Field-induced suppression of the heavy-fermion state in YbRh2Si2

We report dc-magnetization measurements on YbRh2Si2 at temperatures down to 0.04 K, magnetic fields B< or =11.5 T, and under hydrostatic pressure P< or =1.3 GPa. At ambient pressure a kink at B* =9.9 T indicates a new type of field-induced transition from an itinerant to a localized 4f state. This transition is different from the metamagnetic transition observed in other heavy-fermion compounds, as here ferromagnetic rather than antiferromagnetic correlations dominate below B*. Hydrostatic pressure experiments reveal a clear correspondence of B* to the characteristic spin fluctuation temperature determined from specific heat.     

Duality for location problems with unbounded unit balls

Given an optimization problem with a composite of a convex and componentwise increasing function with a convex vector function as objective function, by means of the conjugacy approach based on the perturbation theory, we determine a dual to it. Necessary and sufficient optimality conditions are derived using strong duality. Furthermore, as special case of this problem, we consider a location problem, where the “distances” are measured by gauges of closed convex sets. We prove that the geometric characterization of the set of optimal solutions for this location problem given by Hinojosa and Puerto in a recently published paper can be obtained via the presented dual problem. Finally, the Weber and the minmax location problems with gauges are given as applications.     

Comparison between different duals in multiobjective fractional programming

The present paper is a continuation of [2] where we deal with the duality for a multiobjective fractional optimization problem. The basic idea in [2] consists in attaching an intermediate multiobjective convex optimization problem to the primal fractional problem, using an approach due to Dinkelbach ([6]), for which we construct then a dual problem expressed in terms of the conjugates of the functions involved. The weak, strong and converse duality statements for the intermediate problems allow us to give dual characterizations for the efficient solutions of the initial fractional problem. The aim of this paper is to compare the intermediate dual problem with other similar dual problems known from the literature. We completely establish the inclusion relations between the image sets of the duals as well as between the sets of maximal elements of the image sets.      

Integration of an Equilibrium System in an Enhanced Theory of Bending of Elastic Plates

The complete integral of the system of partial differential equations governing the equilibrium bending of elastic plates with transverse shear deformation and transverse normal strain is constructed by means of complex variable methods. The process helps to elucidate the physical meaning of certain analytic constraints imposed on the asymptotic behavior of the solutions and shows that in the case of an infinite plate, any analytic solution has finite energy if and only if the bending and twisting moments, the transverse shear force, the displacements in vertical planes, and two other characteristic quantities vanish at infinity. An example is discussed to illustrate the theory.