Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

Dallas Bower: a producer for television's early years, 1936-39

Having worked in the film industry as a sound technician and then director, Dallas Bower (1907-99) was appointed in 1936 as one of two senior producers at the start of the BBC Television service. Over the next three years Bower produced as well as directed many ground-breaking live programmes, including the opening-day broadcast on 2 November 1936; the BBC Television Demonstration Film (1937, his only surviving pre-war production); a modern-dress Julius Caesar (1938), in uniforms suggestive of a Fascist disctatorship; Act II of Tristan and Isolde (1938); Patrick Hamilton’s play Rope (1939), utilising extended single camera-shots camera-shots; numerous ballets, among them Checkmate (1938); and ambitious outside broadcasts from the film studios at Denham and Pinewood. Developing the working practices of producing for the theatre, film industry and radio, Bower was a key figure in defining the role of the creative television producer at the start of the medium. Among his innovations, according to his unpublished autobiographical fragment ‘Playback’ (written 1995), was the introduction of a drawn studio plan for the four cameras employed in all live broadcasts from Alexandra Palace. Using Bower’s writings (among them his 1936 book Plan for Cinema), his BECTU History Project interview, the BBC Written Archives and contemporary industry coverage, this article reconstructs the early development of the role of staff television producer in order to consider the questions of autonomy, agency and institutional constraints at the BBC in the pre-war years

Macrofossils and pollen representing forests of the pre-Taupo volcanic eruption (c. 1850 yr BP) era at Pureora and Benneydale, central North Island, New Zealand.

Micro- and macrofossil data from the remains of forests overwhelmed and buried at Pureora and Benneydale during the Taupo eruption (c. 1850 conventional radiocarbon yr BP) were compared. Classification of relative abundance data separated the techniques, rather than the locations, because the two primary clusters comprised pollen and litter/wood. This indicates that the pollen:litter/wood within-site comparisons (Pureora and Benneydale are 20 km apart) are not reliable. Plant macrofossils represented mainly local vegetation, while pollen assemblages represented a combination of local and regional vegetation. However, using ranked abundance and presence/absence data, both macrofossils and pollen at Pureora and Benneydale indicated conifer/broadleaved forest, of similar forest type and species composition at each site. This suggests that the forests destroyed by the eruption were typical of mid-altitude west Taupo forests, and that either data set (pollen or macrofossils) would have been adequate for regional forest interpretation. The representation of c. 1850 yr BP pollen from the known buried forest taxa was generally consistent with trends determined by modern comparisons between pollen and their source vegetation, but with a few exceptions. A pollen profile from between the Mamaku Tephra (c. 7250 yr BP) and the Taupo Ignimbrite indicated that the Benneydale forest had been markedly different in species dominance compared with the forest that was destroyed during the Taupo eruption. These differences probably reflect changes in drainage, and improvements in climate and/or soil fertility over the middle Holocene

Menu labelling and food choice in obese adults: a feasibility study.

BACKGROUND: To date research examining the benefits of menu labelling in the UK is sparse. The aim of the present study was to examine the impact of menu labelling in a UK obese population. METHODS: Using a repeated measures design, 61 patients at a tier 3 weight management service completed four questionnaires to assess their food choice (control) and behaviour change when presented with 3 menu labelling formats (calorie content; nutrient content; and energy expenditure). RESULTS: All three forms of labelling increased participants weight control concerns compared to the control condition. There was a significant difference in content of food ordered in the three menu labelling formats compared to the control condition. The calorie condition had the largest percentage decrease in calories selected followed by energy expenditure and nutrient content. However, no difference was observed between the three conditions in the desire for menu labelling in restaurants to be introduced in the UK. CONCLUSIONS: The findings suggest that menu labelling should be enforced in the UK as it is both beneficial to promoting healthy eating and in demand. This study is the first to examine menu labelling in a UK obese population using energy expenditure equivalents to provide nutritional information

Controlling transmembrane protein concentration and orientation in supported lipid bilayers

The trans-membrane protein – proteorhodopsin (pR) has been incorporated into supported lipid bilayers (SLB). In-plane electric fields have been used to manipulate the orientation and concentration of these proteins, within the SLB, through electrophoresis leading to a 25-fold increase concentration of pR

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers

Acute increase of alpha-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation

This work was supported by grants from the NIH/National Institute of Neurological Disorder and Stroke RO1 NS078165 (to J.R.M.), the Morton Cure Paralysis Fund (to J.R.M.), and the Branfman Family Foundation (to J.M.G.) and by a Dorothea Bennett graduate fellowship (to D.J.B.)

Intake of dietary soy isoflavones in relation to perimenstrual symptoms of Korean women living in the USA

This study was conducted to identify the potential relationship between the dietary intake level of soy isoflavones and perimenstrual symptomatology. The research design was a cross-sectional study. The sample was made up of 84 Korean women living in the USA, aged 28–40 years. The Moos Menstrual Distress Questionnaire (MDQ) and the Food Frequency Questionnaire were used as measurement tools. The soy isoflavone intake was significantly correlated with MDQ scores in the menstrual phase. In conclusion, the beneficial effect of dietary soy isoflavones on certain menstrual symptoms was established, suggesting that soy isoflavones could be one of the dietary factors related to the complexity of premenstrual syndrome (PMS). The positive effect of soy isoflavones on PMS warrants further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72547/1/j.1442-2018.2006.00270.x.pd

Vegetation and edaphic factors influence rapid establishment of distinct fungal communities on former coal-spoil sites

We investigated re-establishment of fungal communities on eight former colliery sites in South Wales following revegetation 22–27 y earlier. Regraded bare coal-spoil was seeded to sheep-grazed grasslands, with saplings planted into coal-spoil for woodlands. Metabarcoding (28S rRNA, D1 region) of soil fungal populations showed that woodland and grassland habitats were clearly divergent but edaphic variables only weakly affected fungal community structure. Root-associated basidiomycetes dominated all habitats, with ectomycorrhizal fungi more abundant in woodlands and Clavariaceae/Hygrophoraceae (‘CHEG’ fungi) in grasslands. The composition of coal-spoil grassland communities resembled that of a typical upland grassland site, suggesting that propagule immigration was not a limiting factor. However, fungal biomass (ergosterol) was 3-fold lower, reflecting high bulk density and poor structure. Re-establishment of fungal communities in coal-spoil soils represents an important barometer of restoration success. From a fungal conservation perspective, such sites represent important refugia for waxcap fungi subject to habitat loss from agricultural intensificatio