GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson\u27s Disease.

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD

Landscape structure planning and the urban forest in polycentric city regions

© Published under licence by IOP Publishing Ltd. The World is continuing to urbanise at an increasing and some say alarming rate, and although urbanism is not uniform in all countries, without a doubt the 21 st century is the century of the Polycentric City Region. By the year 2007, for the first time in history, the world hosted more urban dwellers than rural, and in order to deal with this urban expansion in an environmentally acceptable way, the concept of the "sustainable compact city" was advocated. There is now an increasing canon of research however that suggests that such cities may not be quite as sustainable as they are claimed to be. As a consequence, the concept of "urban green infrastructure", which includes the concept of urban forestry, is being incorporated into new thinking on the landscape structure planning of expanding cities and city regions to ensure that they provide an acceptable quality of life for their inhabitants. The environmental, economic, social, health, well-being and cultural benefits that emanate from such an approach to promoting resilient landscape structure planning are considerable. Such an approach to landscape structure planning is well-able to repair the beneficial relationship that people once had with their landscapes, a relationship that has arguably suffered as our scientific and economic cultures have tended to gain the upper hand in the post-industrial times in which we live. Human beings have had a long, deep, cultural relationship with trees, woodlands and the landscape - a relationship which transcends national cultures. The use of the term "landscape" does not refer to the rather shallow modern concept of 'the landscape as a view", but to the more fundamental concept of "landscape as the composition of our world". Thus it refers to both urban, peri-urban and rural areas, and the urban forest is the prime spatial articulator of a landscape structure plan. Although the words "forest" and "forestry" are now generally understood to be connected with trees, the words have arguably been derived from the Latin word "foris", meaning "out of doors" or "unenclosed land" (Porteous, 1928 p34). Thus urban forestry could be described as the "urban out of doors". This presentation will consider the benefits that can be achieved from developing a viable urban forest structure as the backbone of a polycentric city region landscape structure plan. It will focus upon the Leeds Polycentric City Region in the UK and its emerging Leeds City Region Green and Blue Infrastructure Strategy 2017 - 2036 as a case study

Failure of Lightly Reinforced Concrete Floor Slabs with Planar Edge Restraints under Fire

Accepted versio

Sonoluminescence and sonochemiluminescence from a microreactor

Micromachined pits on a substrate can be used to nucleate and stabilize microbubbles in a liquid exposed to an ultrasonic field. Under suitable conditions, the collapse of these bubbles can result in light emission (sonoluminescence, SL). Hydroxyl radicals (OH*) generated during bubble collapse can react with luminol to produce light (sonochemiluminescence, SCL). SL and SCL intensities were recorded for several regimes related to the pressure amplitude (low and high acoustic power levels) at a given ultrasonic frequency (200 kHz) for pure water, and aqueous luminol and propanol solutions. Various arrangements of pits were studied, with the number of pits ranging from no pits (comparable to a classic ultrasound reactor), to three-pits. Where there was more than one pit present, in the high pressure regime the ejected microbubbles combined into linear (two-pits) or triangular (three-pits) bubble clouds (streamers). In all situations where a pit was present on the substrate, the SL was intensified and increased with the number of pits at both low and high power levels. For imaging SL emitting regions, Argon (Ar) saturated water was used under similar conditions. SL emission from aqueous propanol solution (50 mM) provided evidence of transient bubble cavitation. Solutions containing 0.1 mM luminol were also used to demonstrate the radical production by attaining the SCL emission regions.Comment: http://www.sciencedirect.com/science/article/pii/S1350417712000855; ISSN 1350-417

Quantifying the profile and progression of impairments, activity, participation, and quality of life in people with Parkinson disease : protocol for a prospective cohort study

Background Despite the finding that Parkinson disease (PD) occurs in more than one in every 1000 people older than 60 years, there have been few attempts to quantify how deficits in impairments, activity, participation, and quality of life progress in this debilitating condition. It is unclear which tools are most appropriate for measuring change over time in PD. Methods and design This protocol describes a prospective analysis of changes in impairments, activity, participation, and quality of life over a 12 month period together with an economic analysis of costs associated with PD. One-hundred participants will be included, provided they have idiopathic PD rated I-IV on the modified Hoehn & Yahr (1967) scale and fulfil the inclusion criteria. The study aims to determine which clinical and economic measures best quantify the natural history and progression of PD in a sample of people receiving services from the Victorian Comprehensive Parkinson\u27s Program, Australia. When the data become available, the results will be expressed as baseline scores and changes over 3 months and 12 months for impairment, activity, participation, and quality of life together with a cost analysis. Discussion This study has the potential to identify baseline characteristics of PD for different Hoehn & Yahr stages, to determine the influence of disease duration on performance, and to calculate the costs associated with idiopathic PD. Valid clinical and economic measures for quantifying the natural history and progression of PD will also be identified

Reading into 'Our Words' : a conversation with David Whitlaw

This article considers the contested nature of reading and readership, and divergent meanings ascribed to texts following publication. It asks three important questions. 1: How does the physical or digital form of text, and the mode of geospatial transmission, influence readership and a given reader’s ascription of meaning. 2: Is there any such thing as a misreading of a text? or are all readings of texts valid, regardless of the intended meaning of the author? 3: Can powerful misreadings lead to contested ownership of texts between authors and readers? The article takes as its case study Nova Scotian retiree David Whitlaw’s passionate reading/misreading of Eric Brotchie’s poetic verse Verba Nostrum: For our teachers, published in a previous edition of TXT magazine (Yapp, 2013). In finding the poem in a printed book 5,000 kilometres from Leiden (and 17,500 kilometres from Eric), David’s readership could never have been intended, and his ascription of meaning ever presumed. Following an introduction, the article takes the form of an interview conducted with Mr David Whitlaw by Ms Hilary Drummond (BDMS Alumna 2013) in Greenwich, Nova Scotia in January 2018. Audio files (.mp3) of the full interview and David’s reading of ‘Verba Nostrum’ are available for online readers.Wetensch. publicati

Presynaptic A2A adenosine receptors dampen CB1 cannabinoid receptor-mediated inhibition of corticostriatal glutamatergic transmission

Background and Purpose Both CB1 cannabinoid and A2A adenosine receptors (CB1Rs and A2ARs) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A post-synaptic CB1R-A2AR interaction has already been unraveled, but the presynaptic A2AR-mediated control of presynaptic neuromodulation by CB1Rs remains to be defined. Since the corticostriatal terminals provide the major input of the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions. Experimental Approach Here we employ selective presynaptic tools to study the putative presynaptic interaction between the two neuromodulator systems. Pharmacological manipulation of CB1R and A2AR was carried out in isolated nerve terminals used for flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement, as well as in whole-cell patch-clamp recordings in horizontal corticostriatal slices. Results Flow synaptometry showed that A2AR are extensively co-localized with CB1R-immunopositive corticostriatal terminals, and A2AR co-immunoprecipitated CB1R in these purified terminals. A2AR activation decreased CB1R radioligand binding and decreased the CB1R-mediated inhibition of high-K+-evoked glutamate release in corticostriatal terminals. Accordingly, A2AR activation prevented CB1R-mediated paired-pulse facilitation and attenuated the CB1R-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices. Conclusions and Implications These results show that presynaptic A2AR dampens CB1R-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to shut-down the potent CB1R-mediated presynaptic inhibition, enabling a frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses

Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>The pathological hallmarks of Parkinson's disease (PD) include the presence of alpha-synuclein (α-syn) rich Lewy bodies and neurites and the loss of dopaminergic (DA) neurons of the substantia nigra (SN). Animal models of PD based on viral vector-mediated over-expression of α-syn have been developed and show evidence of DA toxicity to varying degrees depending on the type of virus used, its concentration, and the serotype of vector employed. To date these models have been variable, difficult to reproduce, and slow in their evolution to achieve a desired phenotype, hindering their use as a model for testing novel therapeutics. To address these issues we have taken a novel vector in this context, that can be prepared in high titer and which possesses an ability to produce neuronally-directed expression, with expression dynamics optimised to provide a rapid rise in gene product expression. Thus, in the current study, we have used a high titer chimeric AAV1/2 vector, to express human A53T α-syn, an empty vector control (EV), or green fluorescent protein (GFP), the latter to control for the possibility that high levels of protein in themselves might contribute to damage.</p> <p>Results</p> <p>We show that following a single 2 μl injection into the rat SN there is near complete coverage of the structure and expression of A53T α-syn or GFP appears throughout the striatum. Within 3 weeks of SN delivery of their respective vectors, aggregations of insoluble α-syn were observed in SN DA neurons. The numbers of DA neurons in the SN were significantly reduced by expression of A53T α-syn (52%), and to a lesser extent by GFP (24%), compared to EV controls (both <it>P </it>< 0.01). At the level of the striatum, AAV1/2-A53T α-syn injection produced dystrophic neurites and a significant reduction in tyrosine hydroxylase levels (by 53%, <it>P </it>< 0.01), this was not seen in the AAV1/2-GFP condition.</p> <p>Conclusions</p> <p>In the current implementation of the model, we recapitulate the primary pathological hallmarks of PD, although a proportion of the SN damage may relate to general protein overload and may not be specific for A53T α-syn. Future studies will thus be required to optimise the dose of AAV1/2 employed before fully characterizing this model. The dynamics of the evolution of the pathology however, provide advantages over current models with respect to providing an initial screen to assess efficacy of novel treatments that might prevent/reverse α-syn aggregation.</p