A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins

Using assay-directed fractionation of the venom from the vermivorous cone snail Conus planorbis, we isolated a new conotoxin, designated p114a, with potent activity at both nicotinic acetylcholine receptors and a voltage-gated potassium channel subtype. p114a contains 25 amino acid residues with an amidated C-terminus, an elongated N-terminal tail (six residues), and two disulfide bonds (1-3, 2-4 connectivity) in a novel framework distinct from other conotoxins. The peptide was chemically synthesized, and its three-dimensional structure was demonstrated to be well-defined, with an R-helix and two 3(10)-helices present. Analysis of a cDNA clone encoding the prepropeptide precursor of p114a revealed a novel signal sequence, indicating that p114a belongs to a new gene superfamily, the J-conotoxin superfamily. Five additional peptides in the J-superfamily were identified. Intracranial injection of p114a in mice elicited excitatory symptoms that included shaking, rapid circling, barrel rolling, and seizures. Using the oocyte heterologous expression system, p114a was shown to inhibit both a K+ channel subtype (Kv1.6, IC50) 1.59 mu M) and neuronal (IC50 = 8.7 mu M for alpha 3 beta 4) and neuromuscular (IC50 = 0.54 mu M for alpha 1 beta 1 is an element of delta) subtypes of the nicotinic acetylcholine receptor ( nAChR). Similarities in sequence and structure are apparent between the middle loop of p114a and the second loop of a number of alpha-conotoxins. This is the first conotoxin shown to affect the activity of both voltage-gated and ligand-gated ion channels.

Dual-symmetric Lagrangians in quantum electrodynamics: I. Conservation laws and multi-polar coupling

By using a complex field with a symmetric combination of electric and magnetic fields, a first-order covariant Lagrangian for Maxwell's equations is obtained, similar to the Lagrangian for the Dirac equation. This leads to a dual-symmetric quantum electrodynamic theory with an infinite set of local conservation laws. The dual symmetry is shown to correspond to a helical phase, conjugate to the conserved helicity. There is also a scaling symmetry, conjugate to the conserved entanglement. The results include a novel form of the photonic wavefunction, with a well-defined helicity number operator conjugate to the chiral phase, related to the fundamental dual symmetry. Interactions with charged particles can also be included. Transformations from minimal coupling to multi-polar or more general forms of coupling are particularly straightforward using this technique. The dual-symmetric version of quantum electrodynamics derived here has potential applications to nonlinear quantum optics and cavity quantum electrodynamics.

Microbial Fuel Cells: Methodology and Technology

Microbial fuel cell (MFC) research is a rapidly evolving field that lacks established terminology and methods for the analysis of system performance. This makes it difficult for researchers to compare devices on an equivalent basis. The construction and analysis of MFCs requires knowledge of different scientific and engineering fields, ranging from microbiology and electrochemistry to materials and environmental engineering. DescribingMFCsystems therefore involves an understanding of these different scientific and engineering principles. In this paper, we provide a review of the different materials and methods used to construct MFCs, techniques used to analyze system performance, and recommendations on what information to include in MFC studies and the most useful ways to present results.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

Semi-global techniques in image matching and change detection with applications to civil and environmental engineering.

This work of thesis wants to present a dissertation of the wide range of modern dense matching algorithms, which are spreading in different application and research fields, with a particular attention to the innovative “Semi-Global” matching techniques. The choice of develop a semi-global numerical code was justified by the need of getting insight on the variables and strategies that affect the algorithm performances with the primary objective of maximizing the method accuracy and efficiency, and the results level of completeness. The dissertation will consist in the metrological characterization of the proprietary implementation of the semi-global matching algorithm, evaluating the influence of several matching variables and functions implemented in the process and comparing the accuracy and completeness of different results (digital surface models, disparity maps and 2D displacement fields) obtained using our code and other commercial and open-source matching programs in a wide variety of application fields.

Analysis of Acanthamoeba polyphaga surface carbohydrate exposure by FITC-lectin binding and flourescence evaluation

Aims: Characterization of the representative protozoan Acanthamoeba polyphaga surface carbohydrate exposure by a novel combination of flow cytometry and ligand-receptor analysis. Methods and Results: Trophozoite and cyst morphological forms were exposed to a panel of FITC-lectins. Population fluorescence associated with FITC-lectin binding to acanthamoebal surface moieties was ascertained by flow cytometry. Increasing concentrations of representative FITC-lectins, saturation binding and determination of K d and relative Bmax values were employed to characterize carbohydrate residue exposure. FITC-lectins specific for N-acetylglucosamine, N-acetylgalactosamine and mannose/glucose were readily bound by trophozoite and cyst surfaces. Minor incremental increases in FITC-lectin concentration resulted in significant differences in surface fluorescence intensity and supported the calculation of ligand-binding determinants, Kd and relative B max, which gave a trophozoite and cyst rank order of lectin affinity and surface receptor presence. Conclusions: Trophozoites and cysts expose similar surface carbohydrate residues, foremost amongst which is N-acetylglucosamine, in varying orientation and availability. Significance and Impact of the Study: The outlined versatile combination of flow cytometry and ligand-receptor analysis allowed the characterization of surface carbohydrate exposure by protozoan morphological forms and in turn will support a valid comparison of carbohydrate exposure by other single-cell protozoa and eucaryotic microbes analysed in the same manner.

Canadian province-building : the state as educator and entrepreneur in Alberta

This study provides an account and analysis of the development of systems of educational provision In capitalist democracies, especially in connection with the social origin and relative autonony of those systems. Using the case study of Athabasca University, a Canadian distance-education institution in the province of Alberta, the study is a critical work of historical sociology, in which the shifting social role of a system of educational provision during two transitions of a regional political economy is analyzed. Comparative observations are made in reference to other systems of educational provision and organizations, in particular the training department of a large Company based In the same region as the Unversity. The study explores the social origin and relative autonomy of systems of educational provision In relation to educational ideologies, which are themselves associated with social ideologies. Pierre Bourdieu's theoretical construction of "fields of power'' allows for a consideration of power as a relational phenomenon in the study. In other words, power is understood as being exercised in a way that simultaneously takes account of the power of other actors and groups. Fields of power also allow for an analysis of power as it is exercised at various levels of organizations and within society. The study is organized in two phases. First, an account is developed of the historical period in which the Unlversity and the Company were created, but especially the period of establishment for the Unlversity, 1970 - 75. Conclusions are offered concerning the causal associations between the historical antecedents that gave rise to the two organlzations. It is argued that both the University and the Company were established In part to enact the AIberta government's efforts to enhance Its powers within the Canadian federation (a process called province-building), The second phase is concerned with a more recent period of three years, 1993 - 95. By this time, province-building was not as significant a concern for policy-makers, and the organizational responses of the University and the Company reflected this shift. A divergence of practice is observed at the University and the Company, with actors at the Company encouraging the development of collectivist values for employees, while at the University no such overt strategy was followed, The study concludes that a consumerist model of education developed by the University in 1970 - 75 and expanded In 1993 - 95 contributed significantly to the institution's social origin and relative autonomy. The model was used as an Ideology in the earlier period and as a strategy In the later one, serving to forestall the institution's closure during both periods of crisis, though Ieading to ambiguous social outcomes. A consumerist model may on the one hand be progressive in that expanded access to educational opportunities is made possible. On the other hand, the consumerist model will tend increasingly to provide educational services to those social segments that already have access to educational opportunities.

Dominions apart:scandal and sporting mismatch in Australian-South African association football encounters, 1947-1955

South Africa, Australia and New Zealand participated in numerous sporting contests prior to World War Two. These encounters were primarily on cricket pitches and rugby fields. After nearly four decades of negotiations the first Association football matches were played between the three countries in 1947. The first tour of South Africa to Australia and New Zealand was plagued by scandals on and off the pitch, but despite this Australia returned the favour and toured South Africa three years later. Another five years would pass before South African returned to Australia, by which time it was clear that a large gulf had emerged between the two nations in terms of sporting ability and organisational efficiency. This article focuses on the three tours of 1947, 1950 and 1955, dissecting each as they occurred against a backdrop of scandal, organisational inefficiency and sporting mismatch.

Nondestructive index profiling of long period gratings in photonic crystal fibres

A numerical model of a long period grating in photonic crystal fibre fabricated by an electric arc is proposed that allows for the spectral characterisation of the grating. In the combination with the suggested model of the photonic crystal and the experimentally recorded grating growth it is used to find the index change induced by the electric arc.

Alzheimer’s disease and the eye

Dementia, including Alzheimer’s disease (AD), is a major disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of ß-amyloid (Aß) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary response to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances of complex visual functions such as reading, visuospatial function, and in the naming and identification of objects. Many of these changes are controversial with conflicting data in the literature and no ocular or visual feature can be regarded as particularly diagnostic of AD. In addition, some pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. The optometrist has a role in helping a patient with AD, if it is believed that signs and symptoms of the disease are present, so as to optimize visual function and improve the quality of life. (J Optom 2009;2:103-111 ©2009 Spanish Council of Optometry)

Solid-phase combinatorial chemistry and scintillation proximity assays

The Scintillation Proximity Assay (SPA) is a method that is frequently used to detect and quantify the strength of intermolecular interactions between a biological receptor and ligand molecule in aqueous media. This thesis describes the synthesis of scintillant-tagged-compounds for application in a novel cell-based SPA. A series of 4-functianlised-2,5-diphenyloxazole molecules were synthesised. These 4-functionalised-2,5-diphenyloxazoles were evaluated by Sense Proteomic Ltd. Accordingly, the molecules were evaluated for the ability to scintillate in the presence of ionising radiation. In addition, the molecules were incorporated into liposomal preparations which were subsequently evaluated for the ability to scintillate in the presence of ionising radiation. The optimal liposomal preparation was introduced into the membrane of HeLa cells that were used successfully in a cell-based SPA to detect and quantify the uptake of [14C]methionine. This thesis also describes the synthesis and subsequent polymerisation of novel poly(oxyethylene glycol)-based monomers to form a series of new polymer supports. These Poly(oxyethylene glycol)-polymer (POP) supports were evaluated for the ability to swell and mass-uptake in a variety of solvents, demonstrating that POP-supports exhibit enhanced solvent compatibilities over several commercial resins. The utility of POP-supports in solid-phase synthesis was also demonstrated successfully. The incorporation of (4’-vinyl)-4-benzyl-2,5-diphenyloxazole in varying mole percentage into the monomer composition resulted in the production of chemically functionalised scintillant-containing poly(oxyethylene glycol) polymer (POP-Sc) supports. These materials are compatible with both aqueous and organic solvents and scintillate efficiently in the presence of ionising radiation. The utility of POP-Sc supports in solid-phase synthesis and subsequent in-situ SPA to detect and quantify, in real-time, the kinetic progress of a solid-phase reaction was exemplified successfully.In addition, POP-Sc supports were used successfully both in solid-phase combinatorial synthesis of a peptide nucleic acid (PNA)-library and subsequent screening of this library for the ability to hybridise with DNA, which was labelled with a suitable radio-isotape. This data was used to identify the dependence of the number and position of complimentary codon pairs upon the extent of hybridisation. Finally, a further SPA was used to demonstrate the excellent compatibility of POP-Sc supports for use in the detection and quantification of enzyme assays conducted within the matrix of the POP-Sc support.

Deformation and failure of welded steels used in offshore constructions

Hydrocarbons are the most common form of energy used to date. The activities involving exploration and exploitation of large oil and gas fields are constantly in operation and have extended to such hostile environments as the North Sea. This enforces much greater demands on the materials which are used, and the need for enhancing the endurance of the existing ones which must continue parallel to the explorations. Due to their ease in fabrication, relatively high mechanical properties and low costs, steels are the most widely favoured material for the construction of offshore platforms. The most critical part of an offshore structure prone to failure are the welded nodal joints, particulary those which are used within the vicinity of the splash zones. This is an area of high complex stress concentrations, varying mechanical and metallurgical properties in addition to severe North Sea environmental conditions. The main are of this work has been concerned with the durability studies of this type of steel, based on the concept of the worst case analysis, consisting of combinations of welds of varying qualities, various degrees of stress concentrations and the environmental conditions of stress corrosion and hydrogen embrittlement. The experiments have been designed to reveal significance of defects as sites of crack initiation in the welded steels and the extent to which stress corrosion and hydrogen embrittlement will limit their durability. This has been done for various heat treatments and in some experiments deformation has been forced through the welded zone of the specimens to reveal the mechanical properties of the welds themselves to provide data for finite element simulations. A comparison of the results of these simulations with the actual deformation and fracture behaviour has been done to reveal the extent to which both mechanical and metallurgical factors control behaviour of the steels in the hostile environments of high stress, corrosion, and hydrogen embrittlement at their surface.

The visual cortex in Alzheimer disease:laminar distribution of the pathological changes in visual areas V1 and V2

Alzheimer’s disease (AD) is an important neurodegenerative disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of ?-amyloid (A?) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary responses to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances in complex visual tasks such as reading, visuospatial function, and in the naming and identification of objects. In addition, pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. To better understand degeneration of the visual cortex in AD, the laminar distribution of the SP and NFT was studied in visual areas V1 and V2 in 18 cases of AD which varied in disease onset and duration. In area V1, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In V2, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. The densities of SP in laminae I of V1 and NFT in lamina IV of V2 were negatively correlated with patient age. No significant correlations were observed in any cortical lamina between the density of NFT and disease onset or duration. However, in area V2, the densities of SP in lamina II and lamina V were negatively correlated with disease duration and disease onset respectively. In addition, there were several positive correlations between the densities of SP and NFT in V1 with those in area V2. The data suggest: (1) NFT pathology is greater in area V2 than V1, (2) laminae II/III of V1 and V2 are most affected by the pathology, (3) the formation of SP and NFT in V1 and V2 are interconnected, and (4) the pathology may spread between visual areas via the feed-forward short cortico-cortical connections.

Calcitonin and calcitonin receptor-like receptors:common themes with family B GPCRs?

The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR.

Nondestructive index profiling of long period gratings in photonic crystal fibres

A numerical model of a long period grating in photonic crystal fibre fabricated by an electric arc is proposed that allows for the spectral characterisation of the grating. In the combination with the suggested model of the photonic crystal and the experimentally recorded grating growth it is used to find the index change induced by the electric arc. © Springer Science+Business Media B.V. 2007.