Physical and Chemical Characterization of Therapeutic Iron Containing Materials: A Study of Several Superparamagnetic Drug Formulations with the β-FeOOH or Ferrihydrite Structure

The effectiveness of therapeutically used iron compounds is related to their physical and chemical properties. Four different iron compounds used in oral, intravenous, and intramuscular therapy have been examined by X-ray powder diffraction, iron-57 Mössbauer spectroscopy, transmission electron microscopy, BET surface area measurement, potentiometric titration and studied through dissolution kinetics determinations using acid, reducing and chelating agents. All compounds are nanosized with particle diameters, as determined by X-ray diffraction, ranging from 1 to 4.1 nm. The superparamagnetic blocking temperatures, as determined by Mössbauer spectroscopy, indicate that the relative diameters of the aggregates range from 2.5 to 4.1 nm. Three of the iron compounds have an akaganeite-like structure, whereas one has a ferrihydrite-like structure. As powders the particles form large and dense aggregates which have a very low surface area on the order of 1 m²?g^?1. There is evidence, however, that in a colloidal solution the surface area is increased by two to three orders of magnitude, presumably as a result of the break up of the aggregates. Iron release kinetics by acid, chelating and reducing agents reflect the high surface area, the size and crystallinity of the particles, and the presence of the protective carbohydrate layer coating the iron compound. Within a physiologically relevant time period, the iron release produced by acid or large chelating ligands is small. In contrast, iron is rapidly mobilized by small organic chelating agents, such as oxalate, or by chelate-forming reductants, such as thioglycolate.

     

An Aromatic Dyad Motif in Dye Decolourising Peroxidases Has Implications for Free Radical Formation and Catalysis

Dye decolouring peroxidases (DyPs) are the most recent class of heme peroxidase to be discovered. On reacting with H₂O₂, DyPs form a high-valent iron(IV)-oxo species and a porphyrin radical (Compound I) followed by stepwise oxidation of an organic substrate. In the absence of substrate, the ferryl species decays to form transient protein-bound radicals on redox active amino acids. Identification of radical sites in DyPs has implications for their oxidative mechanism with substrate. Using a DyP from Streptomyces lividans, referred to as DtpA, which displays low reactivity towards synthetic dyes, activation with H₂O₂ was explored. A Compound I EPR spectrum was detected, which in the absence of substrate decays to a protein-bound radical EPR signal. Using a newly developed version of the Tyrosyl Radical Spectra Simulation Algorithm, the radical EPR signal was shown to arise from a pristine tyrosyl radical and not a mixed Trp/Tyr radical that has been widely reported in DyP members exhibiting high activity with synthetic dyes. The radical site was identified as Tyr374, with kinetic studies inferring that although Tyr374 is not on the electron-transfer pathway from the dye RB19, its replacement with a Phe does severely compromise activity with other organic substrates. These findings hint at the possibility that alternative electron-transfer pathways for substrate oxidation are operative within the DyP family. In this context, a role for a highly conserved aromatic dyad motif is discussed.     

Absence of localization in a class of Schrödinger operators with quasiperiodic potential

We prove that a class of discrete Schrödinger operators with a quasiperiodic potential taking only a finite number of values, exhibits purely continuous spectrum; in particular they cannot have localized eigenvectors.Groupe de Recherche 048 of C.N.R.S.     

Thermodynamics for the zero-level set of the Brownian bridge

The random set of instants where the Brownian bridge vanishes is constructed in terms of a random branching process. The Hausdorff measure supported by this set is shown to be equivalent to the partition function of a special class of disordered systems. This similarity is used to show rigorously the existence of a phase transition for this particular class of disordered systems. Moreover, it is shown that at high temperature the specific free energy has the strong self-averaging property and that at low temperature it has no self-averaging property. The unicity at high-temperature and the existence of many limits at low temperature are established almost surely in the disorder.Work supported by the Swiss National Science Foundation     

Robust prediction and interpolation for vector stationary processes

Summary Robust multivariate prediction and interpolation problems for statistically contaminated vector valued second order stationary processes are considered. The statistical contamination is modeled by requiring that the spectral density matrices of the processes lie within certain nonparametric classes. Both prediction and interpolation are then formalized as games whose saddle point solutions are sought. Finally, such solutions are found and analyzed, for two specific multivariate spectral classes.Research supported by the Air Force Office of Scientific Research under Grants AFOSR-83-0229 and AFOSR-82-0030     

Auction algorithms for network flow problems: A tutorial introduction

This paper surveys a new and comprehensive class of algorithms for solving the classical linear network flow problem and its various special cases such as shortest path, max-flow, assignment, transportation, and transhipment problems. The prototype method, from which the other algorithms can be derived, is the auction algorithm for the assignment problem. This is an intuitive method that operates like a rel auction where persons compete for objects by raising their prices through competitive bidding; the prices can be viewed as dual variables. Conceptually, auction algorithms represent a significant departure from the cost improvement idea that underlies primal simplex and dual ascent methods; at any one iteration, they may deteriorate both the primal and the dual cost. Auction algorithms perform very well for several important types of problems, both in theory and in practice, and they are also well suited for parallel computation.     

On the Distribution of Activity Time in PERT

In PERT analysis the activity-time distribution is assumed to be a beta distribution, and the mean and variance of the activity time are estimated on the basis of the ‘pessimistic’, ‘most likely’ and ‘optimistic’ completion times, which are subjectively determined by an analyst. In this paper, on the basis of the study of the PERT assumptions, we present an improvement of these estimates. It is also shown that, by means of additional reasonable assumptions, the activity-time distribution in PERT analysis may be essentially simplified.     

On the Douglas—Rachford splitting method and the proximal point algorithm for maximal monotone operators

This paper shows, by means of an operator called asplitting operator, that the Douglas—Rachford splitting method for finding a zero of the sum of two monotone operators is a special case of the proximal point algorithm. Therefore, applications of Douglas—Rachford splitting, such as the alternating direction method of multipliers for convex programming decomposition, are also special cases of the proximal point algorithm. This observation allows the unification and generalization of a variety of convex programming algorithms. By introducing a modified version of the proximal point algorithm, we derive a new,generalized alternating direction method of multipliers for convex programming. Advances of this sort illustrate the power and generality gained by adopting monotone operator theory as a conceptual framework.This paper is drawn largely from the dissertation research of the first author. The dissertation was performed at M.I.T. under the supervision of the second author, and was supported in part by the Army Research Office under grant number DAAL03-86-K-0171, and by the National Science Foundation under grant number ECS-8519058.     

Dual coordinate step methods for linear network flow problems

We review a class of recently-proposed linear-cost network flow methods which are amenable to distributed implementation. All the methods in the class use the notion of-complementary slackness, and most do not explicitly manipulate any global objects such as paths, trees, or cuts. Interestingly, these methods have stimulated a large number of newserial computational complexity results. We develop the basic theory of these methods and present two specific methods, the-relaxation algorithm for the minimum-cost flow problem, and theauction algorithm for the assignment problem. We show how to implement these methods with serial complexities of O(N ³ logNC) and O(NA logNC), respectively. We also discuss practical implementation issues and computational experience to date. Finally, we show how to implement-relaxation in a completely asynchronous, chaotic environment in which some processors compute faster than others, some processors communicate faster than others, and there can be arbitrarily large communication delays.Supported by Grant NSF-ECS-8217668 and by the Army Research Office under grant DAAL03-86-K-0171. Thanks are due to David Castañon, Paul Tseng, and Jim Orlin for their helpful comments.