Identification of the region of non-A beta component (NAC) of alzheimer's disease amyloid responsible for its aggregation and toxicity

The non-beta-amyloid (Aß) component of Alzheimer's disease amyloid (NAC) and its precursor a-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and a-synuclein both form ß-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3±18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8±18) and NAC(8±16) are toxic, whereas NAC(12±18), NAC(9±16) and NAC(8±15) are not. Circular dichroism indicates that none of the peptides displays ß-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce ß sheet, fragments NAC(8±18) and NAC(8±16) both form ß-sheet structure. Only NAC(8±18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8±16 of NAC, equivalent to residues 68±76 in a-synuclein, comprise the region crucial for toxicity.

English Trade Mark Law in the Eighteenth Century: Blanchard v Hill Revisited - Another 'Case of Monopolies'?

The decision of Lord Hardwicke LC in Blanchard v Hill in 1742 is the earliest reported case on the equitable jurisdiction to grant injunctive relief against trade mark piracy. The ambiguous manner in which the case was reported led to the decision being interpreted as either the basis of equitable jurisdiction or a denial of jurisdiction. This article seeks to establish the background to the case, what actually happened, and the immediate impact of the decision. The scene is set, however, in a parallel symbolic universe – heraldry – because in 1740, the officers of arms were confronted with a trade mark case.

The Masculine Habitus as 'Distributed Cognition': A Case Study of 5- to 6-Year-Old Boys in an English Inner-City, Multi-Ethnic Primary School

This article provides a case study demonstrating the active role that 5- to 6-year-old boys in an English inner-city, multi-ethnic primary school play in the appropriation and reproduction of their masculine identities. It is argued that the emphasis on physicality, violence and racism found among the boys cannot be understood without reference to the immediate contexts of the local community and the school within which they are located. In making this argument the article draws upon and applies the concept of the habitus and develops this with the notion of 'distributed cognition' as proposed in sociocultural theory. Some of the implications of this analysis for working with boys in early years settings are discussed in the conclusion.

Celtic languages in European Higher Education: CRAMLAP - Celtic, Regional and Minority Languages Abroad Project

The Celtic, Regional and Minority Languages Abroad
Project (CRAMLAP) is funded by the European Commission
to research the provision and pedagogy of regional
and minority languages outside their national borders in
Europe. The teaching of Celtic languages across Europe
was the focus in year one (2003-2004). This article summarizes
the qualitative data received in response to
questionnaires sent to institutions across Europe offering
Celtic Studies. Responses indicated that Celtic Studies
are quite widely available across Europe. The languages
are taught in comparative linguistics, linguistics and English
departments, with few dedicated Celtic departments
or sections outside the Celtic countries. Irish is supported
abroad by Irish government grant aid which will
become more widely available in the immediate future.
Many of the teachers have considerable experience, but
limited pedagogic training. The lack of suitable teaching
resources is the most commonly expressed concern.

Tyrosine phosphorylated SOCS-3 inhibits STAT activation but binds p120-RasGAP and activates Ras

Suppressors of cytokine signalling (SOCS, also known as CIS and SSI) are encoded by immediate early genes that act in a feedback loop to inhibit cytokine responses and activation of 'signal transducer and activator of transcription' (STAT). Here we show that SOCS-3 is strongly tyrosine-phosphorylated in response to many growth factors, including interleukin-2 (IL-2), erythropoietin (EPO), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The principal phosphorylation sites on SOCS-3 are residues 204 and 221 at the carboxy terminus, and upon phosphorylation tyrosine 221 interacts with the Ras inhibitor p120 RasGAP. After IL-2 stimulation, phosphorylated SOCS-3 strongly inhibits STAT5 activation but, by binding to RasGAP, maintains activation of extracellular-signal-regulated kinase (ERK). A tyrosine mutant of SOCS-3 still blocks STAT phosphorylation, but also strongly inhibits IL-2-dependent activation of ERK and cell proliferation. Moreover, it also inhibits EPO- and PDGF-induced proliferation and ERK activation. Therefore, although SOCS proteins inhibit growth-factor responses, tyrosine phosphorylation of SOCS-3 can ensure cell survival and proliferation through the Ras pathway.

The chemoattractants, IL-8 and formyl-methionyl-leucyl-phenylalanine, regulate granulocyte colony-stimulating factor signaling by inducing suppressor of cytokine signaling-1 expression

Suppressors of cytokine signaling (SOCS) are encoded by immediate early genes known to inhibit cytokine responses in a classical feedback loop. SOCS gene expression has been shown to be induced by many cytokines, growth factors, and innate immune stimuli, such as LPS. In this paper, we report that the chemoattractants, IL-8 and fMLP, up-regulate SOCS1 mRNA in human myeloid cells, primary human neutrophils, PBMCs, and dendritic cells. fMLP rapidly up-regulates SOCS1, whereas the induction of SOCS1 upon IL-8 treatment is delayed. IL-8 and fMLP did not signal via Jak/STATs in primary human macrophages, thus implicating the induction of SOCS by other intracellular pathways. As chemoattractant-induced SOCS1 expression in neutrophils may play an important role in regulating the subsequent response to growth promoting cytokines like G-CSF, we investigated the effect of chemoattractant-induced SOCS1 on cytokine signal transduction. We show that pretreatment of primary human neutrophils with fMLP or IL-8 blocks G-CSF-mediated STAT3 activation. This study provides evidence for cross-talk between chemoattractant and cytokine signal transduction pathways involving SOCS proteins, suggesting that these chemotactic factors may desensitize neutrophils to G-CSF via rapid induction of SOCS1 expression.

BSP -Style Computation: A Semantic Investigation

A BSP (Bulk Synchronous Parallelism) computation is characterized by the generation of asynchronous messages in packages during independent execution of a number of processes and their subsequent delivery at synchronization points. Bundling messages together represents a significant departure from the traditional ‘one communication at a time’ approach. In this paper the semantic consequences of communication packaging are explored. In particular, the BSP communication structure is identified with a general form of substitution—predicate substitution. Predicate substitution provides a means of reasoning about the synchronized delivery of asynchronous communications when the immediate programming context does not explicitly refer to the variables that are to be updated (unlike traditional operations, such as the assignment $x := e$, where the names of the updated variables can be extracted from the context). Proofs of implementations of Newton's root finding method and prefix sum are used to illustrate the practical application of the proposed approach.

Politicians, elections and catastrophe: the general election of 1847

Over the last decade, much new research has appeared on the subject of the Great Irish Famine but, remarkably, a major political event during the famine - the 1847 general election - has received virtually no mention. Recent work on politics in this period has tended to concentrate on political reaction in Britain rather than Ireland. The aim of this article is to examine the response of Irish politicians to the famine during the general election of 1847. The main source has been the political addresses and nomination speeches of most of the 140 candidates. The evidence from this material shows that, although the famine was an important matter in many constituencies, it was not the dominant issue countrywide. Various proposals to deal with the famine emerged, but there was an absence of agreed, practical measures to deal with immediate problems. The parties in Ireland failed to create a common platform to challenge the government over its efforts. Ideological constraints played an important part in these failures. The general election of 1847 represents a lost opportunity to tackle some of the effects of the famine.

Comparing whole-link travel time models used in DTA

In a model commonly used in dynamic traffic assignment the link travel time for a vehicle entering a link at time t is taken as a function of the number of vehicles on the link at time t. In an alternative recently introduced model, the travel time for a vehicle entering a link at time t is taken as a function of an estimate of the flow in the immediate neighbourhood of the vehicle, averaged over the time the vehicle is traversing the link. Here we compare the solutions obtained from these two models when applied to various inflow profiles. We also divide the link into segments, apply each model sequentially to the segments and again compare the results. As the number of segments is increased, the discretisation refined to the continuous limit, the solutions from the two models converge to the same solution, which is the solution of the Lighthill, Whitham, Richards (LWR) model for traffic flow. We illustrate the results for different travel time functions and patterns of inflows to the link. In the numerical examples the solutions from the second of the two models are closer to the limit solutions. We also show that the models converge even when the link segments are not homogeneous, and introduce a correction scheme in the second model to compensate for an approximation error, hence improving the approximation to the LWR model.

Detection of a Red Supergiant Progenitor Star of a Type II-Plateau Supernova

We present the discovery of a red supergiant star that exploded as supernova 2003gd in the nearby spiral galaxy M74. The Hubble Space Telescope (HST) and the Gemini Telescope imaged this galaxy 6 to 9 months before the supernova explosion, and subsequent HST images confirm the positional coincidence of the supernova with a single resolved star that is a red supergiant of 8+4-2 solar masses. This confirms both stellar evolution models and supernova theories predicting that cool red supergiants are the immediate progenitor stars of type II-plateau supernovae.

Luminous blue variables as the progenitors of supernovae with quasi-periodic radio modulations

The interaction between supernova ejecta and circumstellar matter, arising from previous episodes of mass loss, provides us with a means of constraining the progenitors of supernovae. Radio observations of a number of supernovae show quasi-periodic deviations from a strict power-law decline at late times. Although several possibilities have been put forward to explain these modulations, no single explanation has proven to be entirely satisfactory. Here we suggest that Luminous blue variables undergoing S-Doradus type variations give rise to enhanced phases of mass loss that are imprinted on the immediate environment of the exploding star as a series of density enhancements. The variations in mass loss arise from changes in the ionization balance of Fe, the dominant ion that drives the wind. With this idea, we find that both the recurrence timescale of the variability and the amplitude of the modulations are in line with the observations. Our scenario thus provides a natural, single-star explanation for the observed behaviour that is, in fact, expected on theoretical grounds.

Identification and Development of Enzymes Associated With the Sperm Inner Acrosomal Membrane and Their Function during Fertilization

In order for mammalian fertilization to transpire, spermatozoa must transit through the female reproductive tract and penetrate the outer investments of the oocyte: the cumulus oophorus and the zona pellucida. In order to penetrate the oocyte, spermatozoa must undergo the acrosome reaction. The acrosome reaction results in the exposure of the inner acrosomal membrane (IAM) and proteins that coat it to the extracellular environment. After the acrosome reaction, the IAM becomes the leading edge of spermatozoa undergoing progressive movement. Thus the enzymes which effect lysis of the oocyte investments ought to be located on the IAM. An objective of this study was to identify and characterize enzymatic activity detected on the IAM and provide evidence that they play a role in fertilization. This study also describes procedures for fractionating spermatozoa and isolating the IAM and proteins on its intra- and extra-vesicular surfaces, and describes their development during male gametogenesis. Since the IAM is exposed to the extracellular environment and oviductal milieu after the acrosome reaction, this study also sought to characterize interactions and relationships between factors in the oviductal environment and the enzymes identified on the IAM. The data presented provide evidence that MMP2 and acrosin are co-localized on the IAM, originate from the Golgi apparatus in gametogenesis, and suggest they cooperate in their function. Their localization and results of in vitro fertilization suggests they have a function in zona pellucida penetration. The data also provide evidence that plasminogen, originating from the oviductal epithelium and/or cumulus-oocyte complex, is present in the immediate environment of sperm-egg initial contact and penetration. Additionally, plasminogen interacts with MMP2 and enhances its enzymatic action on the IAM. The data also provide evidence that MMP2 has an important function in penetration of the cumulus oophorus. Holistically, this thesis provides evidence that enzymes on the IAM, originating from the Golgi apparatus in development, have an important function in penetration of the outer investments of the oocyte, and are aided in penetration by plasminogen in the female reproductive tract.

Finding Common Ground: A Critical Review of Land Use and Resource Management Policies in Ontario, Canada and their Intersection with First Nations

This article provides an in-depth analysis of selective land use and resource management policies in the Province of Ontario, Canada. It examines their relative capacity to recognize the rights of First Nations and Aboriginal peoples and their treaty rights, as well as their embodiment of past Crown–First Nations relationships. An analytical framework was developed to evaluate the manifest and latent content of 337 provincial texts, including 32 provincial acts, 269 regulatory documents, 16 policy statements, and 5 provincial plans. This comprehensive document analysis classified and assessed how current provincial policies address First Nation issues and identified common trends and areas of improvement. The authors conclude that there is an immediate need for guidance on how provincial authorities can improve policy to make relationship-building a priority to enhance and sustain relationships between First Nations and other jurisdictions.

Laser annealing of sputtered silicon for wafer-bonding applications

Sputtered silicon is investigated as a bonding layer for transfer of pre-processed silicon layers to various insulating substrates. Although the material appears suitable for low temperature processing, previous work has shown that gas trapped in the pores of the sputtered material is released at temperatures above 350 degrees C and further increases of temperature lead to destruction of any bonded interface. Pre-annealing at 1000 degrees C before bonding drives out gas and/or seals the surface, but for device applications where processing temperatures must be kept below about 300 degrees C, this technique cannot be used. In the current work, we have investigated the effect of excimer laser-annealing to heat the sputtered silicon surface to high temperature whilst minimising heating of the underlying substrate. Temperature profile simulations are presented and the results of RBS, TEM and AFM used to characterise the annealed layers. The results verify that gases are present in the sub-surface layers and suggest that while sealing of the surface is important for suppression of the out-diffusion of gases, immediate surface gas removal may also play a role. The laser-annealing technique appears to be an effective method of treating sputtered silicon, yielding a low roughness surface suitable for wafer bonding, thermal splitting and layer transfer.

Stress resistance and disease resistance in seaweeds: The role of reactive oxygen metabolism

It has become clear over the last 15-20 years that the immediate effect of a wide range of environmental stresses, and of infection, on vascular plants is to increase the formation of reactive oxygen species (ROS) and to impose oxidative stress on the cells. Since 1994, sufficient examples of similar responses in a broad range of marine macroalgae have been described to show that reactive oxygen metabolism also underlies the mechanisms by which seaweeds respond (and become resistant) to stress and infection. Desiccation, freezing, low temperatures, high light, ultraviolet radiation, and heavy metals all tend to result in a gradual and continued buildup of ROS because photosynthesis is inhibited and excess energy results in the formation of singlet oxygen. The response to other stresses (infection or oligosaccharides which signal that infection is occurring, mechanical stress, hyperosmotic shock) is quite different-a more rapid and intense, but short-lived production of ROS, described as an