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

The Southern Wide-Field Gamma-Ray Observatory (SWGO): A Next-Generation Ground-Based Survey Instrument for VHE Gamma-Ray Astronomy

We describe plans for the development of the Southern Wide-field Gamma-ray Observatory (SWGO), a next-generation instrument with sensitivity to the very-high-energy (VHE) band to be constructed in the Southern Hemisphere. SWGO will provide wide-field coverage of a large portion of the southern sky, effectively complementing current and future instruments in the global multi-messenger effort to understand extreme astrophysical phenomena throughout the universe. A detailed description of science topics addressed by SWGO is available in the science case white paper [1]. The development of SWGO will draw on extensive experience within the community in designing, constructing, and successfully operating wide-field instruments using observations of extensive air showers. The detector will consist of a compact inner array of particle detection units surrounded by a sparser outer array. A key advantage of the design of SWGO is that it can be constructed using current, already proven technology. We estimate a construction cost of 54M USD and a cost of 7.5M USD for 5 years of operation, with an anticipated US contribution of 20M USD ensuring that the US will be a driving force for the SWGO effort. The recently formed SWGO collaboration will conduct site selection and detector optimization studies prior to construction, with full operations foreseen to begin in 2026. Throughout this document, references to science white papers submitted to the Astro2020 Decadal Survey with particular relevance to the key science goals of SWGO, which include unveiling Galactic particle accelerators [2-10], exploring the dynamic universe [11-21], and probing physics beyond the Standard Model [22-25], are highlighted in red boldface