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

Critical science plan for the Daniel K. Inouye solar telescope (DKIST)

The National Science Foundation’s Daniel K. Inouye Solar Telescope (DKIST) will revolutionize our ability to measure, understand, and model the basic physical processes that control the structure and dynamics of the Sun and its atmosphere. The first-light DKIST images, released publicly on 29 January 2020, only hint at the extraordinary capabilities that will accompany full commissioning of the five facility instruments. With this Critical Science Plan (CSP) we attempt to anticipate some of what those capabilities will enable, providing a snapshot of some of the scientific pursuits that the DKIST hopes to engage as start-of-operations nears. The work builds on the combined contributions of the DKIST Science Working Group (SWG) and CSP Community members, who generously shared their experiences, plans, knowledge, and dreams. Discussion is primarily focused on those issues to which DKIST will uniquely contribute

The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.

BackgroundSubstantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.ObjectiveWe sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.MethodsGenotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.ResultsWe found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.ConclusionThese findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS