Analysing the impact of iron dysmetabolism on regional metal ion distribution in the brain

An Iron Overload and an H-Ferritin Deficient Mouse Model were used to examine the impact of disrupted iron metabolism on the brain. Brain sections were imaged and compared using Synchrotron μXRF spectroscopy. Quantitative measurement of the relative metal ion concentrations for iron, copper and zinc were made across selected regions of interest in the brain. It was generally found that metal ion concentrations of iron and zinc decreased in specific regions in the Iron Overload condition compared with the control, with copper increasing in only one region. Few regions differed in metal ion concentration between the H-Ferritin Deficient Model and the control. The three conditions exhibited similar / identical results for metal ion concentrations in many brain regions, indicating the validity of the method used for comparison between samples. It is clear that there exists a complex relationship between these trace metal

People with aphasia creating an aphasia friendly website: The DMU4 experience

People with aphasia creating an aphasia friendly website: The DMU4 experience Bixley,M., DMU4, Hall, R., Weale, R., Collingwood, J., Marshall, F. & Hamilton, C. Background Information The DMU4 Conversation group is part of Aphasia Leicester; a community based, voluntary sector, long term support organisation for People with Aphasia (PWA). Members of DMU4 have experienced being unable to access information about their condition because of the way in which the information is presented. These personal experiences are supported by research such as the Care Quality Commission’s (2011) report that suggested that only 40% of social services in Britain provided information in an accessible way for PWA post stroke. In 2011, DMU4 created a leaflet about aphasia that was designed to be used in acute hospitals to educate stroke survivors, relatives and hospital staff about aphasia (Bixley et al, 2011). This leaflet has been distributed to hospitals, surgeries and Speech and Language Therapy Departments in Leicestershire and Rutland. Last year DMU4 decided that they would like to embark on a new project; creating a website about aphasia that was also accessible to PWA. Method The group decided that there were three main factors that needed to guide the construction and structure of the website. Firstly, people with aphasia would appear on the website as aphasia experts. Secondly, navigation around the website should be aphasia friendly, based on visual images and accessible written language. Lastly, members of DMU4 would retain copyright over their own images. For this reason, the site was hosted on “Our DMU Commons” a self organising space that allows users to co construct their own website using open source software. The content of the website was agreed through group discussions. Following these discussions, nine DMU4 members attended a whole day filming session in which their perceptions of aphasia were recorded. Films were then transcribed and edited into eleven themes using a grounded approach. Skeat & Perry (2007) suggest this approach is useful when investigating information that is not available anywhere else, such as the information presented in this website. Informed consent was elicited through discussions, meetings, film and website screenings and signed agreement. Results and discussion The DMU4 website project has two tangible outcomes. The first is that the site will be available to people who want to learn about aphasia. The second is that the resource will be available for Speech and Language Therapy students. Learning activities will enable students to practise recognising and understand aphasia from the perspective of those who live with the loss of language post stroke. The practices of DMU4 are rooted firmly in the social approach to aphasia therapy (Pound, Parr, Lindsay and Woolf, 2000). It is hoped that the website’s third, less measurable, outcome will be a contribution to overcoming the attitudinal and informational barriers that are experienced by PWA post stoke. References BIXLEY, M., DMU4 & HAMILTON, C. (2011) Aphasia – an information leaflet designed by people with aphasia. British Aphasiology Society Biennial International Conference Book of Abstracts, 12. CARE QUALITY COMMISSION (2011) Supporting life after stroke: A review of services for people who have had a stroke and their carers. London: Care Quality Commission. SKEAT, J. & PERRY, A. (2008). Grounded theory as a method for research in speech and language therapy. International Journal of Language and Communication Disorders, 43, 2, 95-109. POUND, C., PARR, S., LINDSAY, J. & WOOLF, C. (2000) Beyond Aphasia: Therapies for Living with Communication Disability. Bicester: Winslow

Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1-42).

Atypical low-oxidation-state iron phases in Alzheimer's disease (AD) pathology are implicated in disease pathogenesis, as they may promote elevated redox activity and convey toxicity. However, the origin of low-oxidation-state iron and the pathways responsible for its formation and evolution remain unresolved. Here we investigate the interaction of the AD peptide β-amyloid (Aβ) with the iron storage protein ferritin, to establish whether interactions between these two species are a potential source of low-oxidation-state iron in AD. Using X-ray spectromicroscopy and electron microscopy we found that the co-aggregation of Aβ and ferritin resulted in the conversion of ferritin's inert ferric core into more reactive low-oxidation-states. Such findings strongly implicate Aβ in the altered iron handling and increased oxidative stress observed in AD pathogenesis. These amyloid-associated iron phases have biomarker potential to assist with disease diagnosis and staging, and may act as targets for therapies designed to lower oxidative stress in AD tissue

A New Ant Species of the Genus Tetramorium Mayr, 1855 (Hymenoptera: Formicidae) from Saudi Arabia, with a Revised Key to the Arabian Species

Tetramorium amalae sp. n. is described and illustrated from Saudi Arabia based on two worker caste specimens collected in Al Bahah region. The new species belongs to the T. shilohense group and appears to be closely related to T. dysderke Bolton from Nigeria. T. amalae is distinguished by having well-developed frontal carinae, smaller eyes, greater head length and width, greater pronotal width, and the petiole node is longer than broad. Tetramorium latinode Collingwood & Agosti is recorded for the first time from Saudi Arabia and for only the second time since the original description. The worker caste of T. latinode is redescribed and illustrated using scanning electron micrographs to facilitate recognition and the gyne is described for the first time with observations given on species relationships, biology and habitat. A revised key to the nineteen Tetramorium species recorded from Arabian Peninsula based on worker castes is provided. Tetramorium bicarinatum (Nylander) is recorded for the first time from Saudi Arabia. It is suggested that T. amalae and T. latinode are endemic to the Arabian Peninsula

Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy

Neuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson’s disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues

Nilpotent orbits and codimension-two defects of 6d N=(2,0) theories

We study the local properties of a class of codimension-2 defects of the 6d N=(2,0) theories of type J=A,D,E labeled by nilpotent orbits of a Lie algebra \mathfrak{g}, where \mathfrak{g} is determined by J and the outer-automorphism twist around the defect. This class is a natural generalisation of the defects of the 6d theory of type SU(N) labeled by a Young diagram with N boxes. For any of these defects, we determine its contribution to the dimension of the Higgs branch, to the Coulomb branch operators and their scaling dimensions, to the 4d central charges a and c, and to the flavour central charge k.Comment: 57 pages, LaTeX2

Iron biochemistry is correlated with amyloid plaque morphology in an established mouse model of Alzheimer’s disease

A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aβ. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Aβ-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD

Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies

Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid beta; or alpha-synuclein. Ex vivo tissue and in vitro systems were investigated, showing the capability to identify metal oxidation states, probe local chemical environments, and localize metal-peptide binding sites. Synchrotron experiments showed that the chemical reduction of ferric (Fe3+) iron and cupric (Cu2+) copper can occur in vitro after incubating each metal in the presence of Aβ for one week, and to a lesser extent for ferric iron incubated with α-syn. Nanoscale chemical speciation mapping of Aβ-Fe complexes revealed a spatial heterogeneity in chemical reduction of iron within individual aggregates. Mass spectrometry allowed the determination of the highest-affinity binding region in all four metal-biomolecule complexes. Iron and copper were coordinated by the same N-terminal region of Aβ, likely through histidine residues. Fe3+ bound to a C-terminal region of α-syn, rich in aspartic and glutamic acid residues, and Cu2+ to the N-terminal region of alpha;-syn. Elucidating the biochemistry of these metal-biomolecule complexes and identifying drivers of chemical reduction processes for which there is evidence ex-vivo, are critical to the advanced understanding of disease aetiology

Metal ion binding to the amyloid beta monomer studied by native top-down FTICR mass spectrometry

Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of the full-length amyloid β (1-42) monomer with a range of (patho)physiologically relevant metal cations using native Fourier transform ion cyclotron resonance mass spectrometry and three different fragmentation methods—collision-induced dissociation, electron capture dissociation, and infrared multiphoton dissociation—all yielding consistent results. Amyloid β is of particular interest as its oligomerization and aggregation are major events in the etiology of Alzheimer’s disease, and it is known that interactions between the peptide and bioavailable metal cations have the potential to significantly damage neurons. Those metals which exhibited the strongest binding to the peptide (Cu2+, Co2+, Ni2+) all shared a very similar binding region containing two of the histidine residues near the N-terminus (His6, His13). Notably, Fe3+ bound to the peptide only when stabilized toward hydrolysis, aggregation, and precipitation by a chelating ligand, binding in the region between Ser8 and Gly25. We also identified two additional binding regions near the flexible, hydrophobic C-terminus, where other metals (Mg2+, Ca2+, Mn2+, Na+, and K+) bound more weakly—one centered on Leu34, and one on Gly38. Unexpectedly, collisional activation of the complex formed between the peptide and [CoIII(NH3)6]3+ induced gas-phase reduction of the metal to CoII, allowing the peptide to fragment via radical-based dissociation pathways. This work demonstrates how native mass spectrometry can provide new insights into the interactions between amyloid β and metal cations

On classical finite and affine W-algebras

This paper is meant to be a short review and summary of recent results on the structure of finite and affine classical W-algebras, and the application of the latter to the theory of generalized Drinfeld-Sokolov hierarchies.Comment: 12 page