Ciguatoxins: Cyclic polyether modulators of voltage-gated Iion channel function

Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na+-dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.

Gaussian operator bases for correlated fermions

We formulate a general multi-mode Gaussian operator basis for fermions, to enable a positive phase-space representation of correlated Fermi states. The Gaussian basis extends existing bosonic phase-space methods to Fermi systems and thus allows first-principles dynamical or equilibrium calculations in quantum many-body Fermi systems. We prove the completeness of the basis and derive differential forms for products with one- and two-body operators. Because the basis satisfies fermionic superselection rules, the resulting phase space involves only c-numbers, without requiring anticommuting Grassmann variables. Furthermore, because of the overcompleteness of the basis, the phase-space distribution can always be chosen positive. This has important consequences for the sign problem in fermion physics.

Quinolactacins revisited: from lactams to imide and beyond

Chemical analysis of a solid phase fermentation of an Australian Penicillium citrinum strain has returned all known examples of a rare class of N-methyl quinolone lactams, quinolactacins A2 (1), B2 (2), C2 (3) and Al (4), together with the new quinolactacins B1 (5), C1 (6), D1 (7) and D2 (8), and the novel derivatives quinolonimide (9) and quinolonic acid (10). Complete stereostructures were assigned to all these compounds by detailed spectroscopic analysis and chemical interconversion. Carefully controlled and monitored decomposition studies have confirmed that quinolactacins readily undergo C-3 epimerization and oxidation, and under appropriate conditions convert to quinolonimide and quinolonic acid. Mechanisms for key transformations are proposed. The decomposition studies suggested that only quinolactacins A2 (1) and B2 (2) are genuine natural products, with all other isolated compounds being decomposition artefacts. Quinolactacins C1 (6), C2 (3), and the racemic mixture of quinolactacins D1/D2 (8/7) all displayed notable cytotoxic activity.

Expression of apoptotic regulatory molecules in renal cell carcinoma: Elevated expression of Fas ligand

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO- 1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.

Grumbling, voting, demonstrating, and rioting: ''Rationality'' and decision-making in intergroup conflict

An individual faced with intergroup conflict chooses A from a vast array of possible actions, ranging from grumbling among ingroup friends to voting and demonstrating to rioting and revolution. The present paper conceptualises these intergroup choices as rationally shaped by perceptions of the benefits and costs associated with the action (expectancy-value processes). However, in presenting a model of agentic normative influence, it is argued that in intergroup contexts group-level costs and benefits play a critical role in individuals' decision-making. In the context of English-French conflict in Quebec, in Canada, four studies provide evidence that group-level costs and benef influence individuals' decision-making in intergro conflict; that the individual level of analysis need mediate the group level of analysis; that group-level co and benefits mediate the relationship between soc identity and intentions to engage in collective action; a that perceptions of outgroup and ingroup norms for inte group behaviours are relatively invariant and predictal related to perceptions of the group- and individual-le, benefits and costs associated with individualistic vers collective actions. By modelling the relationship betwe group norms and group-level costs and benefits, soc psychologists may begin to address the processes th underlie identity-behaviour relationships in collecti action and intergroup conflict.

CULTURA ORGANIZACIONAL: UM ESTUDO SOBRE O SISTEMA DE VALORES DE UMA MULTINACIONAL NO BRASIL

Este trabalho apresenta o tema CULTURA ORGANIZACIONAL: UM ESTUDO SOBRE O SISTEMA DE VALORES DE UMA MULTINACIONAL NO BRASIL . O eixo central da pesquisa é discutir a cultura organizacional global da multinacional sua relação com a cultura organizacional local da subsidiária no Brasil, bem como as relações de compartilhamento. Para isto, utiliza-se como objeto de estudo uma empresa multinacional alemã do segmento de produtos esportivos com subsidiária no Brasil. Com intuito de responder ao objetivo do trabalho foi realizado um estudo de caso único, descritivo explicativo, em uma empresa multinacional alemã instalada na cidade de São Paulo. O caso é composto por 62 sujeitos, 07 gestores e 55 funcionários administrativos que trabalham na subsidiária brasileira. Como resultado obteve-se a idéia de que a cultura organizacional é um fator relevante na sociedade pós-industrial globalizada e é necessário que as empresas multinacionais compreendam a cultura nacional do país onde desejam instalar-se e entendam como administrar as diversidades culturais de cada país.(AU)

ESCOLHAS E DECISÕES: ESTUDO DO PROCESSO PARTICIPATIVO EM ORGANIZAÇÕES DA ECONOMIA SOLIDÁRIA

As últimas décadas, no caso brasileiro, foram marcadas pela predominância da estabilidade econômica e desregulamentação estatal no campo da economia, desconsiderando o impacto na vida das pessoas. Quebras e falências são constatadas como resultado desse processo. Aos trabalhadores surge a oportunidade, com muito esforço, de modelos alternativos nas relações de trabalho. Aparece nesse contexto, o novo discurso da Economia Solidária que preza por práticas autogestionadas. As Empresas Recuperadas são enquadradas dentro desse novo discurso. Entretanto, nas Empresas Recuperadas e nos empreendimentos da Economia Solidária, o espaço fértil proporcionado no campo da subjetividade enfrenta um dilema objetivo. Em sua batalha pela sobrevivência e sustentação, a organização deverá adotar práticas burocráticas e poderá desencantar o espaço da participação. Resulta disso, um dilema entre a objetividade, que a gestão demanda, e a subjetividade que o discurso da Economia Solidária exige. Nessa dissertação, propõe-se que a participação permite um efeito psicológico na medida em que assegura uma inter-relação contínua entre o funcionamento das instituições e as qualidades e atitudes das pessoas que atuam em seu interior. Escolhas e decisões, dessa forma, se colocam como processo que compõe a categoria da participação. Como os trabalhadores das Organizações da Economia Solidária participam do processo de escolhas e decisões em um sistema coletivo e cooperativo de trabalho? Essa é a pergunta central desta pesquisa, que tem por objetivo analisar o processo de escolhas e decisões em organizações da Economia Solidária. Nesse intuito realizou-se um estudo de caso por meio da metodologia da pesquisa-ação de uma empresa recuperada no interior de São Paulo. A pesquisa-ação é um tipo de pesquisa social, com base empírica, que é concebida e realizada em estreita associação com uma ação ou resolução de um problema. Esse problema, no contexto do estudo de caso, foi a concepção de um processo de formação de funcionários para futuros cooperados. A trajetória da discussão foi realizada com acompanhamento de um Grupo Tarefa composto por membros (celetistas e cooperados) da organização. A análise dos resultados foi construída a partir da fundamentação teórica convergindo em três categorias, que compõe o processo de participação, dentro de uma organização da Economia Solidária: Eu comigo (EUCMG), Eu com o(s) outro(s) (EUCOU) e Eu na Organização (EUORG). Os resultados mostram que a Empresa estudada não pode ser considerada como autogestionada e está fundamentada em práticas elitizadas. Há poucas práticas coletivas e se divide em classes internas (chão-defábrica e staff). Contudo, reconhece-se um grande esforço para chegar a uma nova prática de gestão coletiva. A participação se dá dentro de aspectos formais (assembléia) com predominância de assuntos burocráticos que não passaram por apropriação coletiva em sua construção. A educatividade ilumina o caminho processual, rompendo com visões finalísticas e alcançando uma sustentabilidade para a organização.(AU)

OS CONSUMIDORES DE BAIXA RENDA A COMUNICAÇÃO NO SETOR DE HIGIENE PESSOAL, PERFUMARIA E COSMÉTICOS.

Os consumidores de baixa renda pertencentes às classes C, D e E, representam 77% da população brasileira, uma fatia de mercado até então desvalorizadas pelas empresas. Após o Plano Real estes consumidores aumentaram sua participação na aquisição de produtos e serviços, e hoje correspondem a aproximadamente 45% do consumo brasileiro. Visando atender essa grande parcela da população muitas empresas passaram a desenvolver produtos com preços inferiores, mas com qualidade confiável. O estudo investigará o potencial mercadológico destes consumidores e terá como foco principal apresentar as estratégias de comunicação desenvolvidas pelas empresas de higiene pessoal, perfumaria e cosméticos, cujos produtos são destinados aos consumidores de baixa renda.

Strategic ambiguity as a rhetorical resource for enabling multiple interests

The literature on ambiguity reflects contradictory views on its value as a resource or a problem for organizational action. In this longitudinal empirical study of ambiguity about a strategic goal, we examined how strategic ambiguity is used as a discursive resource by different organizational constituents and how that is associated with collective action around the strategic goal. We found four rhetorical positions, each of which drew upon strategic ambiguity to construct the strategic goal differently according to whether the various constituents were asserting their own interests or accommodating wider organizational interests. However, we also found that the different constituents maintained these four rhetorical positions simultaneously over time, enabling them to shift between their own and other’s interests rather than converging upon a common interest. These findings are used to develop a conceptual framework that explains how strategic ambiguity might serve as a resource for different organizational constituents to assert their own interests whilst also enabling collective organizational action, at least of a temporary nature.

Effect of n-3 fatty acids on the antitumour effects of cytotoxic drugs

Background: n-3 fatty acids are increasingly being administered to cancer patients for the treatment of cachexia, and it is thus important to know of any potential interactions with ongoing cytotoxic drug therapy. Materials and methods: For this reason eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were administered to mice bearing the cachexia-inducing MAC16 colon adenocarcinoma, and the effect of epothilone, gemcitabine, 5-fluorouracil and cyclophosphamide on tumour growth and body weight determined. Results: Epothilone alone had a minimal effect on tumour growth rate, but this was potentiated by DHA, while for 5-fluorouracil and cyclophosphamide tumour growth inhibition was enhanced by EPA. The antitumour effect of gemcitabine was not altered by either fatty acid. EPA arrested the development of cachexia, while DHA had no effect and the same was true for their effect on tumour growth rate. The anticachectic effect of EPA was only seen in combination with 5-fluorouracil. Conclusion: These results suggest that n-3 fatty acids do not interfere with the action of chemotherapy and may potentiate the effect of certain agents.

[Bmim]Br-3 as a new reagent for regioselective mono-bromination of activated aromatics under solvent-free conditions

Reaction of activated aromatics containing phenols, naphthol, methoxynaphthalenes, anisole etc. with 1-butyl-3-methylimidazolium tribromide ([Bmim]Br-3) under solvent-free conditions, selectively gave the corresponding monobromination products with excellent yields.

[bmim]Br3 as a new reagent for regioselective monobromination of arylamines under solvent-free conditions

Reaction of arylamines with 1-butyl-3-methylimidazolium tribromide ([bmim]Br3) under solvent-free conditions, gave selectively the corresponding monobromination products with excellent, yields.

Bioreaction and separation in preparative batch chromatographic columns : the hydrology of lactose to yield glucose,galactose and oligosaccharides

The initial aim of this project was to improve the performance of a chromatographic bioreactor-separator (CBRS). In such a system, a dilute enzyme solution is pumped continuously through a preparative chromatographic column, while pulses of substrate are periodically injected on to the column. Enzymic reaction and separation are therefore performed in a single unit operation. The chromatographic columns used were jacketed glass columns ranging from 1 to 2 metres long with an internal diameter of 1.5 cm. Linking these columns allowed 1, 2, 3 and 4 metre long CBRS systems to be constructed. The hydrolysis of lactose in the presence of β~galactosidase was the reaction of study. From previous work at Aston University, there appeared to be no difficulties in achieving complete lactose hydrolysis in a CBRS. There did, however, appear to be scope for improving the separative performance, so this was adopted as an initial goal. Reducing the particle size of the stationary phase was identified as a way of achieving this improvement. A cation exchange resin was selected which had an average particle size of around half that previously used when studying this reaction. A CBRS system was developed which overcame the operational problems (such as high pressure drop development) associated with use of such a particle size. A significant improvement in separative power was achieved. This was shown by an increase in the number of theoretical plates (N) from about 500 to about 3000 for a 2 metre long CBRS, coupled with higher resolution. A simple experiment with the 1 metre column showed that combined bioreaction and separation was achievable in this system. Having improved the separative performance of the system, the factors affecting enzymic reaction in a CBRS were investigated; including pulse volume and the degree of mixing between enzyme and substrate. The progress of reaction in a CBRS was then studied. This information was related to the interaction of reaction and separation over the reaction zone. The effect of injecting a pulse over a length of time as in CBRS operation was simulated by fed batch experiments. These experiments were performed in parallel with normal batch experiments where the substrate is mixed almost instantly with the enzyme. The batch experiments enabled samples to be taken every minute and revealed that reaction is very rapid. The hydrodynamic characteristics of the two injector configurations used in CBRS construction were studied using Magnetic Resonance Imaging, combined with hydrodynamic calculations. During the optimisation studies, galactooligosaccharides (GOS) were detected as intermediates in the hydrolysis process. GOS are valuable products with potential and existing applications in food manufacture (as nutraceuticals), medicine and drug targeting. The focus of the research was therefore turned to GOS production. A means of controlling reaction to arrest break down of GOS was required. Raising temperature was identified as a possible means of achieving this within a CBRS. Studies were undertaken to optimise the yield of oligosaccharides, culminating in the design, construction and evaluation of a Dithermal Chromatographic Bioreactor-separator.

Bioreaction and separation in batch chromatographic columns

The objective of this work has been to study the behaviour and performance of a batch chromatographic column under simultaneous bioreaction and separation conditions for several carbohydrate feedstocks. Four bioreactions were chosen, namely the hydrolysis of sucrose to glucose and fructose using the enzyme invertase, the hydrolysis of inulin to fructose and glucose using inulinase, the hydrolysis of lactose to glucose and galactose using lactase and the isomerization of glucose to fructose using glucose isomerase. The chromatographic columns employed were jacketed glass columns ranging from 1 m to 2 m long and the internal diameter ranging from 0.97 cm to 1.97 cm. The stationary phase used was a cation exchange resin (PUROLITE PCR-833) in the Ca2+ form for the hydrolysis and the Mg2+ form for the isomerization reactions. The mobile phase used was a diluted enzyme solution which was continuously pumped through the chromatographic bed. The substrate was injected at the top of the bed as a pulse. The effect of the parameters pulse size, the amount of substrate solution introduced into the system corresponding to a percentage of the total empty column volume (% TECV), pulse concentration, eluent flowrate and the enzyme activity of the eluent were investigated. For the system sucrose-invertase complete conversions of substrate were achieved for pulse sizes and pulse concentrations of up to 20% TECV and 60% w/v, respectively. Products with purity above 90% were obtained. The enzyme consumption was 45% of the amount theoretically required to produce the same amount of product as in a conventional batch reactor. A value of 27 kg sucrose/m3 resin/h for the throughput of the system was achieved. The systematic investigation of the factors affecting the performance of the batch chromatographic bioreactor-separator was carried out by employing a factorial experimental procedure. The main factors affecting the performance of the system were the flowrate and enzyme activity. For the system inulin-inulinase total conversions were also obtained for pulses sizes of up to 20 % TECV and a pulse concentration of 10 % w/v. Fructose rich fractions with 100 % purity and representing up to 99.4 % of the total fructose generated were obtained with an enzyme consumption of 32 % of the amount theoretically required to produce the same amount of product in a conventional batch reactor. The hydrolysis of lactose by lactase was studied in the glass columns and also in an SCCR-S unit adapted for batch operation, in co-operation with Dr. Shieh, a fellow researcher in the Chemical Engineering and Applied Chemistry Department at Aston University. By operating at up to 30 % w/v lactose feed concentrations complete conversions were obtained and the purities of the products generated were above 90%. An enzyme consumption of 48 % of the amount theoretically required to produce the same amount of product in a conventional batch reactor was achieved. On working with the system glucose-glucose isomerase, which is a reversible reaction, the separation obtained with the stationary phase conditioned in the magnesium form was very poor although the conversion obtained was compatible with those for conventional batch reactors. By working with a mixed pulse of enzyme and substrate, up to 82.5 % of the fructose generated with a purity of 100 % was obtained. The mathematical modelling and computer simulation of the batch chromatographic bioreaction-separation has been performed on a personal computer. A finite difference method was used to solve the partial differential equations and the simulation results showed good agreement with the experimental results.

Synthesis and cytotoxity of oxysterols:studies on the A,B ring polyoxygenated sterols

Oxysterols (OS), the polyoxygenated sterols, represent a class of potent regulatory molecules for important biological actions. Cytotoxicity of OS is one of the most important aspects in studies of OS bioactivities. However, studies, the structure-activity relationship (SAR) study in particular, have been hampered by the limited availability of structurally diverse OS in numbers and amounts. The aim of this project was to develop robust synthetic methods for the preparation of polyhydroxyl sterols, thereof, evaluate their cytotoxicity and establish structure-activity relationship. First, we found hydrophobicity of the side chain is essential for 7-HC's cytotoxicity, and a limited number of hydroxyl groups and a desired configuration on the A, B ring are required for a potent cytotoxicity of an OS, after syntheses and tests of a number of 7-HC's analogues against cancer cell lines. Then polyoxygenation of cholesterol A, B rings was explored. A preparative method for the synthesis of four diastereomerically pure cholest-4-en-3,6-diols was developed. Epoxidation on these cholest-4-en-3,6-diols showed that an allyl group exerts an auxiliary role in producing products with desired configuration in syntheses of the eight diastereomerically pure 45-epoxycholestane-3,6-diols. Reduction of the eight 45-epoxycholestane-3,6-diols produced all eight isomers of the cytotoxic 5α-acholestane 3β,5,6β-triol (CT) for the first time. Epoxide ring opening with protic or Lewis acids on the eight 45-epoxycholestane-3,6-diols are carefully studied. The results demonstrated a combination of an acid and a solvent affected the outcomes of a reaction dramatically. Acyl group participation and migration play an important role with numbers of substrates under certain conditions. All the eight 4,5-trans cholestane- 3,4,5,6-tetrols were synthesised through manipulation of acyl participation. Furthermore these reaction conditions were tested when a number of cholestane-3,4, 5,6,7-pentols and other C3-C7 oxygenated sterols were synthesised for the first time. Introduction of an oxygenated functional group through cholest-2-ene derivatives was studied. The elimination of 3-(4-toluenesulfonate) esters showed the interaction between the existing hydroxyls or acyls with the reaction centre often resulted in different products. The allyl oxidation, epoxidation and Epoxide ring opening reactions are investigated with these cholest-2-enes.