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      No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

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          ABSTRACT

          Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre‐eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include ( i) stress‐induced iron dysregulation, and ( ii) its ability to awaken dormant, non‐replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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            Principles that govern the folding of protein chains.

             C ANFINSEN (1973)
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              Persister cells, dormancy and infectious disease.

               Kim Lewis (2006)
              Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.
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                Author and article information

                Contributors
                dbk@manchester.ac.uk
                Journal
                Biol Rev Camb Philos Soc
                Biol Rev Camb Philos Soc
                10.1111/(ISSN)1469-185X
                BRV
                Biological Reviews of the Cambridge Philosophical Society
                Blackwell Publishing Ltd (Oxford, UK )
                1464-7931
                1469-185X
                25 March 2018
                August 2018
                : 93
                : 3 ( doiID: 10.1111/brv.2018.93.issue-3 )
                : 1518-1557
                Affiliations
                [ 1 ] School of Chemistry The University of Manchester, 131 Princess Street Manchester Lancs M1 7DN U.K.
                [ 2 ] The Manchester Institute of Biotechnology The University of Manchester, 131 Princess Street Manchester Lancs M1 7DN U.K.
                [ 3 ] Department of Physiological Sciences Stellenbosch University, Stellenbosch Private Bag X1 Matieland 7602 South Africa
                Author notes
                [* ]Address for correspondence (Tel: +44 161 3064492; E‐mail: dbk@ 123456manchester.ac.uk ).
                Article
                BRV12407 BRV-11-2017-0258.R2
                10.1111/brv.12407
                6055827
                29575574
                © 2018 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 9, Tables: 5, Pages: 40, Words: 38373
                Product
                Funding
                Funded by: National Research Foundation
                Funded by: Biotechnology and Biological Sciences Research Council
                Award ID: BB/L025752/1
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                brv12407
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:23.07.2018

                Ecology

                amyloid, inflammation, iron dysregulation, blood clotting, lps, amplification

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