Alpha-synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cells

Parkinson's disease (PD) is characterized in part by the presence of alpha-synuclein (alpha-syn) rich intracellular inclusions (Lewy bodies). Mutations and multiplication of the alpha-synuclein gene (SNCA) are associated with familial PD. Since Ca2+ dyshomeostasis may play an important role in the pathogenesis of PD, we used fluorimetry in fura-2 loaded SH-SY5Y cells to monitor Ca2+ homeostasis in cells stably transfected with either wild-type alpha-syn, the A53T mutant form, the S129D phosphomimetic mutant or with empty vector (which served as control). Voltage-gated Ca2+ influx evoked by exposure of cells to 50 mM K+ was enhanced in cells expressing all three forms of alpha-syn, an effect which was due specifically to increased Ca2+ entry via L-type Ca2+ channels. Mobilization of Ca2+ by muscarine was not strikingly modified by any of the alpha-syn forms, but they all reduced capacitative Ca2+ entry following store depletion caused either by muscarine or thapsigargin. Emptying of stores with cyclopiazonic acid caused similar rises of [Ca2+](i) in all cells tested (with the exception of the S129D mutant), and mitochondrial Ca2+ content was unaffected by any form of alpha-synuclein. However, only WT alpha-syn transfected cells displayed significantly impaired viability. Our findings suggest that alpha-syn regulates Ca2+ entry pathways and, consequently, that abnormal alpha-syn levels may promote neuronal damage through dysregulation of Ca2+ homeostasis.

Reframing 'crisis' in fair trade coffee production: trajectories of agrarian change in Nicaragua

A focus on crisis provides a methodological window to understand how agrarian change shapes producer engagement in fair trade. This orientation challenges a seperation between the market and development, situating fair trade within global processes that incorporate agrarian histories of social change and conflict. Reframing crisis as a condition of agrarian life, rather than emphasizing its cyclical manifestation within the global economy, reveals how market-driven development encompasses the material conditions of peoples' existence in ambiguous and contradictory ways. Drawing on the case of coffee production in Nicaragua, experiences of crisis demonstrate that greater attention needs to be paid to the socioeconomic and political dimensions of development within regional commodity assemblages to address entrenched power relations and unequal access to land and resources. This questions moral certainties when examining the paradox of working in and against the market, and suggests that a better understanding of specific trajectories of development could improve fair trade's objective of enhancing producer livelihoods.

An obscured tradition: the sonnet and its fourteen-line predecessors

The sonnet in English is usually located as a sixteenth-century innovation, firmly linked to Italian influences, and frequently associated with a distinctively modern consciousness. Yet the speed and comfort with which the form settled into English reflects the fact that the sonnet per se was preceded by a longstanding tradition of 14-line poems in English written in forms derived from French. Indeed, in terms of formal features, the earliest sonnets in English frequently fray into earlier forms, sharing more with the roundel than with later sonnets. This article considers a number of features of style and content that various writers on the sonnet have argued to be characteristic, sometimes definitive, of the sonnet. These features include repetition, formal unity/division of octave and sestet, use of the volta, asymmetry, argument and development, and a preoccupation with contradictions and the self. The article shows that, while it is true that these features are characteristic of many sonnets, they are not peculiarly characteristic of sonnets, and they can all be found in earlier 14-line poems. Furthermore, a number of the earliest sonnets in English do not themselves possess these ‘sonnet-like’ characteristics. The otherness and the modernity of the sonnet have thus been overstated.

Beyond the computer: changing medium from digital to physical

How can organizations use digital infrastructure to realise physical outcomes? The design and construction of London Heathrow Terminal 5 is analysed to build new theoretical understanding of visualization and materialization practices in the transition from digital design to physical realisation. In the project studied, an integrated software solution is introduced as an infrastructure for delivery. The analyses articulate the work done to maintain this digital infrastructure and also to move designs beyond the closed world of the computer to a physical reality. In changing medium, engineers use heterogeneous trials to interrogate and address the limitations of an integrated digital model. The paper explains why such trials, which involve the reconciliation of digital and physical data through parallel and iterative forms of work, provide a robust practice for realizing goals that have physical outcomes. It argues that this practice is temporally different from, and at times in conflict with, building a comprehensive dataset within the digital medium. The paper concludes by discussing the implications for organizations that use digital infrastructures in seeking to accomplish goals in digital and physical media.

Food and Health Forum meeting - nutritional approaches to cardiovascular health: workshop report

This report summarises the proceedings of a meeting held by the Food and Health Forum at the Royal Society of Medicine, London, on 12 October 2011. The objective of the meeting was to highlight nutritional strategies targeted at cardiovascular health. This included a review of the effects of various foods, nutrients and ingredients on maintenance of healthy cholesterol levels, endothelial function and blood pressure

Altitude acts as an environmental filter on phylogenetic composition, traits and diversity in bee communities.

Knowledge about the phylogeny and ecology of communities along environmental gradients helps to disentangle the role of competition-driven processes and environmental filtering for community assembly. In this study, we evaluated patterns in species richness, phylogenetic structure and life-history traits of bee communities along altitudinal gradients in the Alps, Germany. We found a linear decline in species richness and abundance but increasing phylogenetic clustering in communities with increasing altitude. The proportion of social- and ground-nesting species, as well as mean body size and altitudinal range of bee communities, increased with increasing altitude, whereas the mean geographical distribution decreased. Our results suggest that community assembly at high altitudes is dominated by environmental filtering effects, whereas the relative importance of competition increases at low altitudes. We conclude that inherent phylogenetic and ecological species attributes at high altitudes pose a threat for less competitive alpine specialists with ongoing climate change.

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays

Background Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat (‘artificial animal’) applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Results Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. Conclusions We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

Spectral theory of some non-selfadjoint linear differential operators

We give a characterisation of the spectral properties of linear differential operators with constant coefficients, acting on functions defined on a bounded interval, and determined by general linear boundary conditions. The boundary conditions may be such that the resulting operator is not selfadjoint. We associate the spectral properties of such an operator $S$ with the properties of the solution of a corresponding boundary value problem for the partial differential equation $\partial_t q \pm iSq=0$. Namely, we are able to establish an explicit correspondence between the properties of the family of eigenfunctions of the operator, and in particular whether this family is a basis, and the existence and properties of the unique solution of the associated boundary value problem. When such a unique solution exists, we consider its representation as a complex contour integral that is obtained using a transform method recently proposed by Fokas and one of the authors. The analyticity properties of the integrand in this representation are crucial for studying the spectral theory of the associated operator.

Solar ultraviolet-B radiation and vitamin D: a cross-sectional population-based study using data from the 2007 to 2009 Canadian Health Measures Survey

Background: Exposure to solar ultraviolet-B (UV-B) radiation is a major source of vitamin D3. Chemistry climate models project decreases in ground-level solar erythemal UV over the current century. It is unclear what impact this will have on vitamin D status at the population level. The purpose of this study was to measure the association between ground-level solar UV-B and serum concentrations of 25-hydroxyvitamin D (25(OH)D) using a secondary analysis of the 2007 to 2009 Canadian Health Measures Survey (CHMS). Methods: Blood samples collected from individuals aged 12 to 79 years sampled across Canada were analyzed for 25(OH)D (n=4,398). Solar UV-B irradiance was calculated for the 15 CHMS collection sites using the Tropospheric Ultraviolet and Visible Radiation Model. Multivariable linear regression was used to evaluate the association between 25(OH)D and solar UV-B adjusted for other predictors and to explore effect modification. Results: Cumulative solar UV-B irradiance averaged over 91 days (91-day UV-B) prior to blood draw correlated significantly with 25(OH)D. Independent of other predictors, a 1 kJ/m 2 increase in 91-day UV-B was associated with a significant 0.5 nmol/L (95% CI 0.3-0.8) increase in mean 25(OH)D (P =0.0001). The relationship was stronger among younger individuals and those spending more time outdoors. Based on current projections of decreases in ground-level solar UV-B, we predict less than a 1 nmol/L decrease in mean 25(OH)D for the population. Conclusions: In Canada, cumulative exposure to ambient solar UV-B has a small but significant association with 25(OH)D concentrations. Public health messages to improve vitamin D status should target safe sun exposure with sunscreen use, and also enhanced dietary and supplemental intake and maintenance of a healthy body weight.

Association mapping of partitioning loci in barley

Background: Association mapping, initially developed in human disease genetics, is now being applied to plant species. The model species Arabidopsis provided some of the first examples of association mapping in plants, identifying previously cloned flowering time genes, despite high population sub-structure. More recently, association genetics has been applied to barley, where breeding activity has resulted in a high degree of population sub-structure. A major genotypic division within barley is that between winter- and spring-sown varieties, which differ in their requirement for vernalization to promote subsequent flowering. To date, all attempts to validate association genetics in barley by identifying major flowering time loci that control vernalization requirement (VRN-H1 and VRN-H2) have failed. Here, we validate the use of association genetics in barley by identifying VRN-H1 and VRN-H2, despite their prominent role in determining population sub-structure. Results: By taking barley as a typical inbreeding crop, and seasonal growth habit as a major partitioning phenotype, we develop an association mapping approach which successfully identifies VRN-H1 and VRN-H2, the underlying loci largely responsible for this agronomic division. We find a combination of Structured Association followed by Genomic Control to correct for population structure and inflation of the test statistic, resolved significant associations only with VRN-H1 and the VRN-H2 candidate genes, as well as two genes closely linked to VRN-H1 (HvCSFs1 and HvPHYC). Conclusion: We show that, after employing appropriate statistical methods to correct for population sub-structure, the genome-wide partitioning effect of allelic status at VRN-H1 and VRN-H2 does not result in the high levels of spurious association expected to occur in highly structured samples. Furthermore, we demonstrate that both VRN-H1 and the candidate VRN-H2 genes can be identified using association mapping. Discrimination between intragenic VRN-H1 markers was achieved, indicating that candidate causative polymorphisms may be discerned and prioritised within a larger set of positive associations. This proof of concept study demonstrates the feasibility of association mapping in barley, even within highly structured populations. A major advantage of this method is that it does not require large numbers of genome-wide markers, and is therefore suitable for fine mapping and candidate gene evaluation, especially in species for which large numbers of genetic markers are either unavailable or too costly.

Mathematics applied to the climate system: outstanding challenges and recent progress

The societal need for reliable climate predictions and a proper assessment of their uncertainties is pressing. Uncertainties arise not only from initial conditions and forcing scenarios, but also from model formulation. Here, we identify and document three broad classes of problems, each representing what we regard to be an outstanding challenge in the area of mathematics applied to the climate system. First, there is the problem of the development and evaluation of simple physically based models of the global climate. Second, there is the problem of the development and evaluation of the components of complex models such as general circulation models. Third, there is the problem of the development and evaluation of appropriate statistical frameworks. We discuss these problems in turn, emphasizing the recent progress made by the papers presented in this Theme Issue. Many pressing challenges in climate science require closer collaboration between climate scientists, mathematicians and statisticians. We hope the papers contained in this Theme Issue will act as inspiration for such collaborations and for setting future research directions.