Prion protein self-peptides modulate prion interactions and conversion

<p>Abstract</p> <p>Background</p> <p>Molecular mechanisms underlying prion agent replication, converting host-encoded cellular prion protein (PrP^C) into the scrapie associated isoform (PrP^Sc), are poorly understood. Selective self-interaction between PrP molecules forms a basis underlying the observed differences of the PrP^Cinto PrP^Scconversion process (agent replication). The importance of previously peptide-scanning mapped ovine PrP self-interaction domains on this conversion was investigated by studying the ability of six of these ovine PrP based peptides to modulate two processes; PrP self-interaction and conversion.</p> <p>Results</p> <p>Three peptides (octarepeat, binding domain 2 -and C-terminal) were capable of inhibiting self-interaction of PrP in a solid-phase PrP peptide array. Three peptides (N-terminal, binding domain 2, and amyloidogenic motif) modulated prion conversion when added before or after initiation of the prion protein misfolding cyclic amplification (PMCA) reaction using brain homogenates. The C-terminal peptides (core region and C-terminal) only affected conversion (increased PrP^resformation) when added before mixing PrP^Cand PrP^Sc, whereas the octarepeat peptide only affected conversion when added after this mixing.</p> <p>Conclusion</p> <p>This study identified the putative PrP core binding domain that facilitates the PrP^C-PrP^Scinteraction (not conversion), corroborating evidence that the region of PrP containing this domain is important in the species-barrier and/or scrapie susceptibility. The octarepeats can be involved in PrP^C-PrP^Scstabilization, whereas the N-terminal glycosaminoglycan binding motif and the amyloidogenic motif indirectly affected conversion. Binding domain 2 and the C-terminal domain are directly implicated in PrP^Cself-interaction during the conversion process and may prove to be prime targets in new therapeutic strategy development, potentially retaining PrP^Cfunction. These results emphasize the importance of probable PrP^C-PrP^Cand required PrP^C-PrP^Scinteractions during PrP conversion. All interactions are probably part of the complex process in which polymorphisms and species barriers affect TSE transmission and susceptibility.</p

Rapid and discriminatory diagnosis of scrapie and BSE in retro-pharyngeal lymph nodes of sheep

BACKGROUND: Diagnosis based on prion detection in lymph nodes of sheep and goats can improve active surveillance for scrapie and, if it were circulating, for bovine spongiform encephalopathy (BSE). With sizes that allow repetitive testing and a location that is easily accessible at slaughter, retropharyngeal lymph nodes (RLN) are considered suitable organs for testing. Western blotting (WB) of brain homogenates is, in principle, a technique well suited to both detect and discriminate between scrapie and BSE. In this report, WB is developed for rapid diagnosis in RLN and to study biochemical characteristics of PrP(res). RESULTS: Optimal PrP(res )detection in RLN by WB was achieved by proper tissue processing, antibody choice and inclusion of a step for PrP(res)concentration. The analyses were performed on three different sheep sources. Firstly, in a study with preclinical scrapie cases, WB of RLN from infected sheep of VRQ/VRQ genotype – VRQ represents, respectively, polymorphic PrP amino acids 136, 154, and 171 – allowed a diagnosis 14 mo earlier compared to WB of brain stem. Secondly, samples collected from sheep with confirmed scrapie in the course of passive and active surveillance programmes in the period 2002–2003 yielded positive results depending on genotype: all sheep with genotypes ARH/VRQ, VRQ/VRQ, and ARQ/VRQ scored positive for PrP(res), but ARQ/ARQ and ARR/VRQ were not all positive. Thirdly, in an experimental BSE study, detection of PrP(res )in all 11 ARQ/ARQ sheep, including 7 preclinical cases, was possible. In all instances, WB and IHC were almost as sensitive. Moreover, BSE infection could be discriminated from scrapie infection by faster electrophoretic migration of the PrP(res )bands. Using dual antibody staining with selected monoclonal antibodies like 12B2 and L42, these differences in migration could be employed for an unequivocal differentiation between BSE and scrapie. With respect to glycosylation of PrP(res), BSE cases exhibited a greater diglycosylated fraction than scrapie cases. Furthermore, a slight time dependent increase of diglycosylated PrP(res )was noted between individual sheep, which was remarkable in that it occurred in both scrapie and BSE study. CONCLUSION: The present data indicate that, used in conjunction with testing in brain, WB of RLN can be a sensitive tool for improving surveillance of scrapie and BSE, allowing early detection of BSE and scrapie and thereby ensuring safer sheep and goat products

Dual-stage structural response to quenching charge order in magnetite

The Verwey transition in magnetite (Fe_{3}O_{4} ) is the prototypical metal-insulator transition and has eluded a comprehensive explanation for decades. A major element of the challenge is the complex interplay between charge order and lattice distortions. Here we use ultrafast electron diffraction (UED) to disentangle the roles of charge order and lattice distortions by tracking the transient structural evolution after charge order is melted via ultrafast photoexcitation. A dual-stage response is observed in which X_{3}, X_{1}, and Delta5-type structural distortions occur on markedly different timescales of 0.7–3.2 ps and longer than 3.2 ps. We propose that these distinct timescales arise because X_{3}-type distortions strongly couple to the trimeron charge order, whereas the Delta5- distortions are more strongly associated with monoclinic to cubic distortions of the overall lattice. Our work aids in clarifying the charge-lattice interplay using UED method and illustrates the disentanglement of the complex phases in magnetite

Impact of Scotland’s comprehensive, smoke-free legislation on stroke

&lt;p&gt;Background: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overalland by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006.&lt;/p&gt; &lt;p&gt;Methods and Findings: A negative binomial regression model was used to determine whether the introduction of smokefree legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p,0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential cofounders.&lt;/p&gt; &lt;p&gt;Conclusions: Following introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.&lt;/p&gt

Sequential Effects in Judgements of Attractiveness: The Influences of Face Race and Sex

In perceptual decision-making, a person’s response on a given trial is influenced by their response on the immediately preceding trial. This sequential effect was initially demonstrated in psychophysical tasks, but has now been found in more complex, real-world judgements. The similarity of the current and previous stimuli determines the nature of the effect, with more similar items producing assimilation in judgements, while less similarity can cause a contrast effect. Previous research found assimilation in ratings of facial attractiveness, and here, we investigated whether this effect is influenced by the social categories of the faces presented. Over three experiments, participants rated the attractiveness of own- (White) and other-race (Chinese) faces of both sexes that appeared successively. Through blocking trials by race (Experiment 1), sex (Experiment 2), or both dimensions (Experiment 3), we could examine how sequential judgements were altered by the salience of different social categories in face sequences. For sequences that varied in sex alone, own-race faces showed significantly less opposite-sex assimilation (male and female faces perceived as dissimilar), while other-race faces showed equal assimilation for opposite- and same-sex sequences (male and female faces were not differentiated). For sequences that varied in race alone, categorisation by race resulted in no opposite-race assimilation for either sex of face (White and Chinese faces perceived as dissimilar). For sequences that varied in both race and sex, same-category assimilation was significantly greater than opposite-category. Our results suggest that the race of a face represents a superordinate category relative to sex. These findings demonstrate the importance of social categories when considering sequential judgements of faces, and also highlight a novel approach for investigating how multiple social dimensions interact during decision-making

Publication rates of editorial board members in oral health journals

The aim of this study was to measure the publication rate of editorial board members in their board journals and to evaluate associated variables. We evaluated the ten highest-ranked journals according to the 5-year impact factor under ‘Dentistry, Oral Surgery & Medicine’ subject category for 2010, 2011, and 2012. All original research papers with at least one member of the editorial board as author were counted. Final analyses assessed associated variables such as size of the editorial board, number of papers published each year, and each journal’s impact factor. Overall, there was an increase in the average number of articles published from 2010 (115.2 ± 52.2) to 2012 (134.7 ± 47.4). The number and percentage of articles published with editorial board members as authors over the three years did not follow the same pattern, with a slight decrease from 2010 to 2011 and an increase in 2012. The number of articles with editorial board members as authors was significantly higher for journals with impact factors ≥4.0. Journals with a higher impact factor and larger editorial board were associated with higher chances of editorial board members publishing in their respective journals. Participation of editorial board members as authors in publishing varies significantly among journals

Thermal quenches in N=2* plasmas

We exploit gauge/gravity duality to study `thermal quenches' in a plasma of the strongly coupled N=2* gauge theory. Specifically, we consider the response of an initial thermal equilibrium state of the theory under variations of the bosonic or fermionic mass, to leading order in m/T<<1. When the masses are made to vary in time, novel new counterterms must be introduced to renormalize the boundary theory. We consider transitions the conformal super-Yang-Mills theory to the mass deformed gauge theory and also the reverse transitions. By construction, these transitions are controlled by a characteristic time scale \calt and we show how the response of the system depends on the ratio of this time scale to the thermal time scale 1/T. The response shows interesting scaling behaviour both in the limit of fast quenches with T\calt<<1 and slow quenches with T\calt>>1. In the limit that T\calt\to\infty, we observe the expected adiabatic response. For fast quenches, the relaxation to the final equilibrium is controlled by the lowest quasinormal mode of the bulk scalar dual to the quenched operator. For slow quenches, the system relaxes with a (nearly) adiabatic response that is governed entirely by the late time profile of the mass. We describe new renormalization scheme ambiguities in defining gauge invariant observables for the theory with time dependant couplings.Comment: 78 pages, 17 figure

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection

Belowground DNA-based techniques: untangling the network of plant root interactions

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