Cellular mechanisms in prion-mediated neurodegeneration

Prion diseases are fatal neurodegenerative disorders of both humans and other animals. The cause of prion-mediated neurodegeneration by conversion of the normal cellular prion protein (PrPC) to the disease-related isoform (PrPSc) remains unknown. Increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease. PrPC and PrPSc isoforms have been shown to accumulate in cells after proteasome inhibition, leading to increased cell death. The aim of this thesis was to investigate the role of cellular degradation systems, such as the UPS and autophagy, in prion-mediated cell death. In UPS-mediated degradation poly-ubiquitinated substrates get degraded by the 26S proteasome, which comprises a 20S hydrolytic core and a 19S regulatory particle. Using a variety of biochemical methods, I report that abnormal beta-sheet-rich PrP isoforms inhibit the catalytic activity of the 26S proteasome, by specifically inhibiting its beta1 and beta5 proteolytic subunits. Pre-incubating these PrP isoforms with an antibody raised against aggregation intermediates abrogates the inhibitory effect seen, consistent with an ‘oligomeric’ inhibitory species. Using open-gated yeast 20S proteasome mutants and conserved 19S ATPase C-terminal peptides containing an essential motif for gate-opening, this thesis describes findings supporting an inhibitory effect on proteasomal gating rather than a direct inhibitory effect on the active sites of the 20S proteasome. These C-terminal peptides open the gate in a ‘key in a lock’ fashion by docking into inter-subunit pockets in the alpha-ring of the 20S proteasome. In this system, the inhibitory effect of the beta-sheet-rich PrP isoforms may be due to abnormal PrP competing with the C-terminal peptides for the inter-subunit pockets, thereby preventing gate-opening. Proteins are also degraded by autophagy, a degradation pathway that has not been adequately characterised in prion disease. This thesis investigates potential roles autophagy may play in prion disease. Data presented here suggest that a) prions are cleared by autophagy, b) prion-infected cells have higher numbers of autophagosomes compared to uninfected controls, c) induction of autophagy ameliorates cell death after proteasome inhibition, indicating cross-talk between the two protein-degradation pathways, and d) it is up-regulated in vivo at end-stage prion disease

Shaman, Sage, Priest, Prophet and Magician: Exploring the Architecture of the Religious Wise Man

Little attention has been given to the archetype of the wise old man, both by Carl G. Jung and by contemporary scholars indebted to his methodology. This is especially relevant when compared to other common Jungian archetypes such as the ‘hero’, the ‘mother’ and the ‘trickster.’ As such, the wise man can be viewed as a neglected or overlooked figure whose image is so familiar and recognisable that his purpose and representations have not currently received the depth of analysis and explanation that has been given to other archetypal images. This thesis identifies the religious wise man as an important figure within the contexts of culture and religion. Its aim is to not only to explore the ‘archetype’ of the wise man, but to go beyond that rather superficial – and indeed, academically problematic – notion, and determine what I term the ‘architecture’ of the wise man. This architecture consists of the structural elements (social, institutional, historical) and identifiers (costume, calling, education), that separate the wise man, and in particular the religious wise man, from other male ‘archetypal’ figures. In using the term ‘architecture’ I aim to identify the arrangement of concrete elements and characteristics - rather than psychological or inner ‘essences’ - which are significant in the construction and maintenance of the religious wise man figure in specific cultural contexts. The dissertation presents five possible categories of the religious wise man - the shaman, sage, priest, prophet and magician – identifying common elements and distinguishing features that may then be redesigned and adapted in different and unique forms appropriate to each manifestation of the religious wise man. Once these key characteristics are identified, they create a schema that can be employed to classify a range of religious wise man figures into the appropriate category

The Brauer complex and its applications to the Chevalley groups

This thesis, is concerned with the determination of the connected centralizers of semi-simple elements in a Chevalley group. To deal with this problem we shall use the recent work of R. Carter [6] and a new tool for the study of algebraic groups - the so called Brauer complex. This complex has been first defined by J. Humphreys [11] in the context of the modular representation theory of the finite Chevalley groups of universal type. Now, in our version, the Brauer complex can be also used for the ordinary representation theory of the finite Chevalley groups of adjoint type. For, Deligne and Lusztig in their fundamental work [9] have constructed for these groups certain families of irreducible complex representations whose degrees can be obtained if we know what subgroups of the finite Chevalley groups are the connected centralizers of semi-simple elements

Macroporous silicon filters, a versatile platform for NDIR spectroscopic gas sensing in the MIR

© The Author(s) 2019. Published by ECS. This is an open access article distributed under the terms of the Creative CommonsAttribution 4.0 License (CC BY,http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse of the work in anymedium, provided the original work is properly cited.This paper describes the spectroscopic detection of gases using macroporous silicon photonic crystals as narrow filters. The study begins by demonstrating the feasibility of photoelectrochemical etching to fabricate narrow filters along the mid infrared band. Next, we focus on the filter centered on the carbon dioxide fingerprint. The filter response is described for three different cell lengths and concentrations below 1%. Results show a concordance with the reformulated Beer-Lambert law. This can be used to predict the response of the filter for longer path lengths and higher concentrations, showing broad working ranges and compact sizes for CO2. In addition, optical robustness to external variations and long-term stability are also reported. Results are extrapolated to other macroporous silicon filters centered on the absorption spectra of N2O, OCS, NO2 and SO2. Finally, high sensitivity and selectivity is demonstrated by comparing them with some commercial filters.Postprint (published version

Empirical demonstration of CO2 detection using macroporous silicon photonic crystals as selective thermal emitters

This study describes the detection of CO2 using macroporous silicon photonic crystals as thermal emitters. It demonstrates that the reduction of structural nonhomogeneities leads to an improvement of the photonic crystals’ emission. Narrow emission bands (¿~120) located within the R-branch of carbon dioxide were achieved. Measurements were made using a deuterated triglycine sulfate photodetector and the photonic crystals, heated to 400°C, as selective emitters. A gas cell with a CO2 concentration between 0 ppm and 10,000 ppm was installed in the center. Results show high sensibility and selectivity that could be used in current nondispersive infrared devices for improving their features. These results open the door to narrowband emission in the mid-infrared for spectroscopic gas detection.Postprint (author's final draft

Exploring the Simultaneous Effect of Total Ion Concentration and K:Ca:Mg Ratio of the Nutrient Solution on the Growth and Nutritional Value of Hydroponically Grown Cichorium spinosum L.

Nutrient-efficient plants and agricultural systems could tackle issues resulting from conventional agriculture. Spiny chicory (Cichorium spinosum L.), a very adaptive, wild edible vegetable, is gaining commercial interest as a functional food. Floating-raft hydroponics is a method commonly used for the commercial cultivation of leafy vegetables due to numerous advantages compared to soil cultivation. In this paper, the simultaneous effects of different potassium, calcium and magnesium ratios and different electrical conductivity (EC) levels on the growth and mineral composition of hydroponically grown C. spinosum were investigated. Four nutrient solutions (NS) were compared, two NS with low EC (L, 2.4 dS/m) and two with high EC (H, 3.6 dS/m) with K:Ca:Mg ratios of either 50:40:10 or 40:50:10. The results showed no interactions between the two factors. No significant effects were observed on the fresh and dry weight, leaf number and leaf area. High EC levels increased the K content and decreased the Mn and Zn content in the leaf tissues. The 40:50:10 ratio led to increased Ca content in plant tissues. The Nitrate-N was only affected by the EC level and was increased under H conditions, whereas the total-N was not affected

A cross-sectional study of memory and executive functions in patients with sporadic inclusion body myositis

INTRODUCTION: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterised by muscle deposition of various proteins typically associated with Alzheimer's disease and other neurodegenerative diseases. While cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. We aimed to investigate whether cognitive performance of patients with IBM differs from population norms, focussing on cognitive domains affected in early Alzheimer's disease (memory, executive function), and to test whether disease duration and the level of disability of IBM are associated with cognitive function. METHODS: Twenty-four patients with IBM (mean [SD] age 62.0 [7.2] years; disease duration 9.6 [4.8] years) were assessed cross-sectionally on neuropsychological tests covering multiple cognitive domains, including the Preclinical Alzheimer Cognitive Composite (PACC). Performance was compared to published normative data adjusted for age, sex and education (National Alzheimer's Coordinating Center; N = 3268). Associations were examined between PACC score, disease duration and level of disability (assessed using the IBM Functional Rating Scale [IBMFRS]). RESULTS: Across all cognitive tests, group performance was within ±1SD of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, p = 0.87) or IBMFRS total score (ρ = 0.14, p = 0.52). DISCUSSION: Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients, and will be of value for clinicians and patients alike. This article is protected by copyright. All rights reserved

Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders

FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical as

The structure of blocks with a Klein four defect group

We prove Erdmann’s conjecture [16] stating that every block with a Klein four defect group has a simple module with trivial source, and deduce from this that Puig’s finiteness conjecture holds for source algebras of blocks with a Klein four defect group. The proof uses the classification of finite simple groups