Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.

A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

The Sustainability Balanced Scorecard. Linking Sustainability Management to Business Strategy.

The Balanced Scorecard of Kaplan and Norton is a management tool that supports the successful implementation of corporate strategies. It has been discussed and considered widely in both practice and research. By linking operational and non-financial corporate activities with causal chains to the firm's long-term strategy, the Balanced Scorecard supports the alignment and management of all corporate activities according to their strategic relevance. The Balanced Scorecard makes it possible to take into account non-monetary strategic success factors that significantly impact the economic success of a business. The Balanced Scorecard is thus a promising starting-point to also incorporate environmental and social aspects into the main management system of a firm. Sustainability management with the Balanced Scorecard helps to overcome the shortcomings of conventional approaches to environmental and social management systems by integrating the three pillars of sustainability into a single and overarching strategic management tool. After a brief discussion of the different possible forms of a Sustainability Balanced Scorecard the article takes a closer look at the process and steps of formulating a Sustainability Balanced Scorecard for a business unit. Before doing so, the basic conventional approach of the Balanced Scorecard and its suitability for sustainability management will be outlined in brief.

Effect of an attentional strategy on movement-related potentials recorded from subjects with Huntington's disease

Huntington's disease patients perform automatic movements in a bradykinetic manner, somewhat similar to patients with Parkinson's disease. Cortical activity relating to the preparation of movement in Parkinson's disease is significantly improved when a cognitive strategy is used. It is unknown whether patients with Huntington's disease can utilise an attentional strategy, and what effect this strategy would have on the premovement cortical activity. Movement-related potentials were recorded from 12 Huntington's disease patients and controls performing externally cued finger tapping movement, allowing an examination of cortical activity related to movement performance and bradykinesia in this disease. All subjects were tested in two conditions, which differed only by the presence or absence of the cognitive strategy. The Huntington's disease group, unlike controls, did not produce a rising premovement potential in the absence of the strategy. The Huntington's disease group did produce a rising premovement potential for the strategy condition, but the early slope of the potential was significantly reduced compared with the control group's early slope. These results are similar to those found previously with Parkinson's disease patients. The strategy may have put the task, which previously might have been under deficient automatic control, under attentional control. (C) 2002 Movement Disorder Society.

Including disabled children at school: Is it really as simple as 'a, c, d'?

This paper presents and discusses a social justice strategy that may progress inclusion in schools. The framework for this strategy is grounded in the theoretical discussions by Nancy Fraser and Trevor Gale about distributive, redistributive, and recognitive models of social justice. None of these theoretical frameworks, however, in themselves, offer a clear way forward for marginalised and misrecognised groups, such as disabled children, who need both educational resources and recognition in inclusive classrooms. The authors propose, however, that the work of Fraser and Gale combines into a social justice strategy, which consists of three elements (agency, competency, and diversity, or ‘a, c, d’) that can lead to inclusion. When disabled children are provided with the opportunity to exercise their agency, demonstrate their competence, and transform and affirm notions of diversity, then inclusion is more likely to occur in the classroom. Data from two research projects are presented using this framework to illustrate this argument, and the proposed ‘a, c, d’ social justice strategy towards inclusion.

History, an Exit Strategy: The Retrofuture Fabulations of kara lynch

A cartographer constructs a map of an individual creative history, that of the American artist kara lynch, as it emerges in connection to a collective history of African American cultural expression. Positioning history as complex, dynamic systems of interwoven memory networks, the map follows lynch’s traversals through various “zones of cultural haunting”: places where collective memories made invisible through systematic processes of cultural erasure may be recovered and revived. Through these traversals, which are inspired by lynch’s “forever project” Invisible, the map covers such terrains as haunted narratives, mechanisms of abstraction and coding within African American media production, water as an informational technology, the distribution of memory in blood, the dialectics of materiality and immateriality that frame considerations of black subjectivity, and the possibility that place of music might not be the site of sound but instead the social production of memory.

Towards a strategy for the conservation of the freshwater pearl mussel Margaritifera margaritifera in County Donegal, Ireland

This study attempts to identify the habitat requirements of the pearl mussel Margaritifea margaritifera in County Donegal, in north west Ireland, an area with little urban, industrial or intensive agricultural development. No mussels occur in rivers where calcium and conductivity levels are high or where the substratum is predominantly bedrock or fine sediment but it was not possible to distinguish clearly between mussel and non-mussel sites on the basis of ordination analysis. However, rivers which still support mussels and rivers with historical records of mussels are loosely grouped. Rivers which formerly supported mussels but lack living M. margaritifera appear to have suitable habitat for mussels; pearl fishing is the most likely reason for the extinction of these mussel populations. Where population densities are high, for example in locations on the rivers Eske, Clady and Owenea, conservation may necessitate the establishment of reserves. The prospect for the successful reintroduction of mussels into former mussel rivers such as the Finn and Eany Water, where suitable habitat exists and water quality is high, is very good.

A novel dual-fluorescence strategy for functionally validating microRNA targets in 3-prime untranslated regions: regulation of the inward rectifier potassium channel Kir2.1 by miR-212.

Gene targeting by microRNAs is important in health and disease. We developed a functional assay for identifying microRNA targets and applied it to the K+ channel Kir2.1 (KCNJ2) which is dysregulated in cardiac and vascular disorders. The 3'UTR was inserted downstream of the mCherry red fluorescent protein coding sequence in a mammalian expression plasmid. MicroRNA sequences were inserted into the pSM30 expression vector which provides enhanced green fluorescent protein as an indicator of microRNA expression. HEK293 cells were co-transfected with the mCherry-3'UTR plasmid and a pSM30-based plasmid with a microRNA insert. The principle of the assay is that functional targeting of the 3'UTR by the microRNA results in a decrease in the red/green fluorescence intensity ratio as determined by automated image analysis. The method was validated with miR-1, a known downregulator of Kir2.1 expression, and was used to investigate targeting of the Kir2.1 3'UTR by miR-212. Red/green ratio was lower in miR-212-expressing cells compared to non-targeting controls, an effect that was attenuated by mutating the predicted target site. MiR-212 also reduced inward rectifier current and Kir2.1 protein in HeLa cells. This novel assay has several advantages over traditional luciferase-based assays including larger sample size, amenability to time course studies and adaptability to high-throughput screening.

Web-based social movements contesting marketing strategy: Mobilization of multiple actors and rhetorical strategies

Previous studies suggest that marketing strategy is developed and used to mobilise and configure the actions of firm actors, creating a set of stabilising activities focused on the firm–customer dyad. Destabilising forces precipitated by the Internet and associated digital technologies involving contention and disruption by multiple actors are much less prevalent in the marketing literature. The central point we advance is that rather than marketing strategy being a controlled and stabilising force for firms in their relationships with customers, it can often lead to socially produced spaces where consumers and, importantly, other multiple actors form a social movement to actively attempt to destabilise it and contest its legitimacy. Using an innovative research approach, the findings of this study show how social movements proactively enrol and mobilise a wide range of relevant actors into a network of influence. Critical to this are rhetorical strategies, acting as important levers in attempts to destabilise and delegitimise a dominant firm's marketing strategy.

Differential power analysis resistance of Camellia and countermeasure strategy on FPGAs

Security devices are vulnerable to Differential Power Analysis (DPA) that reveals the key by monitoring the power consumption of the circuits. In this paper, we present the first DPA attack against an FPGA implementation of the Camellia encryption algorithm with all key sizes and evaluate the DPA resistance of the algorithm. The Camellia cryptographic algorithm involves several different key-dependent intermediate operations including S-Box operations. In previous research, it was believed that the Camellia is stronger than AES due to the additional Whitening phase protecting the S-Box operation. However, we propose an attack that bypasses the Whitening phase and targets the S-Box. In this paper, we also discuss a lowcost countermeasure strategy to protect the Pre-whitening / Post-whitening and FL function of Camellia using Dual-rail Precharged Logic and to protect against attacks of the S-Box using Random Delay Insertion. © 2009 IEEE.

A biofuel strategy for Ireland with an emphasis on production of biomethane and minimization of land-take

Increasing energy consumption has exerted great pressure on natural resources; this has led to a move towards sustainable energy resources to improve security of supply and to reduce greenhouse gas emissions. However, the rush to the cure may have been made in haste. Biofuels in particular, have a bad press both in terms of competition with good agricultural land for food, and also in terms of the associated energy balance with the whole life cycle analysis of the biofuel system. The emphasis is now very much on sustainable biofuel production; biofuels from wastes and lignocellulosic material are now seen as good sustainable biofuels that affect significantly better greenhouse gas balances as compared with first generation biofuels. Ireland has a significant resource of organic waste that could be a potential source of energy through anaerobic digestion. Ireland has 8% of the cattle population of the EU with less than 1% of the human population; as a result 91% of agricultural land in Ireland is under grass. Residues such as slurries and slaughter waste together with energy crops such as grass have an excellent potential to produce biogas that may be upgraded to biomethane. This biomethane may be used as a natural gas substitute; bio-compressed natural gas may then be an avenue for a biofuel strategy. It is estimated that a maximum potential of 33% of natural gas may be substituted by 2020 with a practical obtainable level of 7.5% estimated. Together with biodiesel from residues the practical obtainable level of this strategy may effect greater than a 5% substitution by energy of transport. The residues considered in this strategy to produce biofuel (excluding grass) have the potential to save 93,000 ha of agricultural land (23% of Irish arable land) when compared to a rapeseed biodiesel strategy. © 2009 Elsevier Ltd. All rights reserved.

Targeting poverty: Lessons from monitoring Ireland's national anti-poverty strategy

In 1997 the Irish government adopted the National Anti-Poverty Strategy (NAPS), a global target for the reduction of poverty which illuminates a range of issues relating to official poverty targets. The Irish target is framed in terms of a relative poverty measure incorporating both relative income and direct measures of deprivation based on data on the extent of poverty from 1994. Since 1994 Ireland has experienced an unprecedented period of economic growth that makes it particularly important to assess whether the target has been achieved, but in doing so we cannot avoid asking some underlying questions about how poverty should be measured and monitored over time. After briefly outlining the nature of the NAPS measure, this article examines trends in poverty in Ireland between 1987 and 1997, Results show that the relative income and deprivation components of the NAPS measure reveal differential trends with increasing relative income poverty, but decreasing deprivation. However, this differential could be due to the fact that the direct measures of deprivation upon which NAPS is based have not been updated to take account of changes in real living standards and increasing expectations. To test whether this is so, we examine the extent to which expectations about living standards and the structure of deprivation have changed over time using confirmatory factor analysis and tests of criterion validity using different definitions of deprivation. Results show that the combined income and deprivation measure, as originally constituted, continues to identify a set of households experiencing generalised deprivation resulting from a lack of resources.

A pseudo-transient solution strategy for the analysis of delamination by means of interface elements

Recent efforts in the finite element modelling of delamination have concentrated on the development of cohesive interface elements. These are characterised by a bilinear constitutive law, where there is an initial high positive stiffness until a threshold stress level is reached, followed by a negative tangent stiffness representing softening (or damage evolution). Complete decohesion occurs when the amount of work done per unit area of crack surface is equal to a critical strain energy release rate. It is difficult to achieve a stable, oscillation-free solution beyond the onset of damage, using standard implicit quasi-static methods, unless a very refined mesh is used. In the present paper, a new solution strategy is proposed based on a pseudo-transient formulation and demonstrated through the modelling of a double cantilever beam undergoing Mode I delamination. A detailed analysis into the sensitivity of the user-defined parameters is also presented. Comparisons with other published solutions using a quasi-static formulation show that the pseudo-transient formulation gives improved accuracy and oscillation-free results with coarser meshes