Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Domain Decomposition Methods for Domain Composition Purpose: Chimera, Overset, Gluing and Sliding Mesh Methods

The final publication is available at link.springer.com via http://dx.doi.org/10.1007/s11831-016-9198-8Domain composition methods (DCM) consist in obtaining a solution to a problem, from the formulations of the same problem expressed on various subdomains. These methods have therefore the opposite objective of domain decomposition methods (DDM). Indeed, in contrast to DCM, these last techniques are usually applied to matching meshes as their purpose consists mainly in distributing the work in parallel environments. However, they are sometimes based on the same methodology as after decomposing, DDM have to recompose. As a consequence, in the literature, the term DDM has many times substituted DCM. DCM are powerful techniques that can be used for different purposes: to simplify the meshing of a complex geometry by decomposing it into different meshable pieces; to perform local refinement to adapt to local mesh requirements; to treat subdomains in relative motion (Chimera, sliding mesh); to solve multiphysics or multiscale problems, etc. The term DCM is generic and does not give any clue about how the fragmented solutions on the different subdomains are composed into a global one. In the literature, many methodologies have been proposed: they are mesh-based, equation-based, or algebraic-based. In mesh-based formulations, the coupling is achieved at the mesh level, before the governing equations are assembled into an algebraic system (mesh conforming, Shear-Slip Mesh Update, HERMESH). The equation-based counterpart recomposes the solution from the strong or weak formulation itself, and are implemented during the assembly of the algebraic system on the subdomain meshes. The different coupling techniques can be formulated for the strong formulation at the continuous level, for the weak formulation either at the continuous or at the discrete level (iteration-by-subdomains, mortar element, mesh free interpolation). Although the different methods usually lead to the same solutions at the continuous level, which usually coincide with the solution of the problem on the original domain, they have very different behaviors at the discrete level and can be implemented in many different ways. Eventually, algebraic- based formulations treat the composition of the solutions directly on the matrix and right-hand side of the individual subdomain algebraic systems. The present work introduces mesh-based, equation-based and algebraicbased DCM. It however focusses on algebraic-based domain composition methods, which have many advantages with respect to the others: they are relatively problem independent; their implicit implementation can be hidden in the iterative solver operations, which enables one to avoid intensive code rewriting; they can be implemented in a multi-code environment

Nonprotein-bound iron and plasma protein oxidative stress at birth.

We previously reported plasma nonprotein-bound iron (NPBI) as a reliable early indicator of intrauterine oxidative stress (OS) and brain injury. We tested the hypothesis that albumin, an NPBI serum carrier, is the major target of NPBI-induced OS. Twenty-four babies were randomly selected from 384 newborns constituting the final cohort of a prospective study undertaken to evaluate the predictive role of NPBI in cord blood for neurodevelopmental outcome. Twelve were selected in the group with lowest NPBI levels (0-1.16 microM) and good neurodevelopmental outcome and 12 in the group with highest NPBI levels (>or=15.2 microM) and poor neurodevelopmental outcome. Protein carbonyl groups were identified in cord blood samples by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and Western blotting with anti-2,4-dinitrophenyl (DNP) antibodies. Two series of immunoreactive spots, corresponding to serum albumin and alpha-fetoprotein, were found only in the group with highest NPBI levels. We found an association between NPBI and carbonylated proteins in babies with highest NPBI levels. Since NPBI may produce hydroxyl radicals through the Fenton reaction, the major target of OS induced by NPBI is its carrier: albumin. Oxidation of albumin can be expected to decrease plasma antioxidant defenses and increase the likelihood of tissue damage due to OS in the newborns

Oxidants in biology: a question of balance

Oxidants, like other aspects of life, involves tradeoffs. Oxidants, whether intentionally produced or by-products of normal metabolism can either mediate a variety of critical biological processes but when present inappropriately cause extensive damage to biological molecules ( DNA, proteins, and lipids). These effects can lead to either damage that is a major contributor to aging and degenerative diseases (or to other diseases such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts) or normal physiological function- tissue repair, defense against pathogens and cellular proliferation. On the other hand the body is equipped with a complex antioxidant/oxidant handling system which includes both enzymatic and nonenzymatic (i.e. small molecules such as flavonoids, ascorbate, tocopherol, and carotenoids) produced endogenously or derived from the diet. This book focuses on how the same molecules can have favorable or noxious effects depending on location, level and timing