Microarray and proteomic analysis of the human alcoholic brain

The superior frontal cortex (SFC) is selectively damaged in chronic alcohol abuse, with localized neuronal loss and tissue atrophy. Regions such as motor cortex show little neuronal loss except in severe co-morbidity (liver cirrhosis or WKS). Altered gene expression was found in microarray comparisons of alcoholic and control SFC samples [1]. We used Western blots and proteomic analysis to identify the proteins that also show differential expression. Tissue was obtained at autopsy under informed, written consent from uncomplicated alcoholics and age- and sex-matched controls. Alcoholics had consumed 80 g ethanol/day chronically (often, 200 g/day for 20 y). Controls either abstained or were social drinkers ( 20 g/day). All subjects had pathological confirmation of liver and brain diagnosis; none had been polydrug abusers. Samples were homogenized in water and clarified by brief centrifugation (1000g, 3 min) before storage at –80°C. For proteomics the thawed suspensions were centrifuged (15000g, 50 min) to prepare soluble fractions. Aliquots were pooled from SFC samples from the 5 chronic alcoholics and 5 matched controls used in the previous microarray study [1]. 2-Dimensional electrophoresis was performed in triplicate using 18 cm format pH 4–7 and pH 6–11 immobilized pH gradients for firstdimension isoelectric focusing. Following second-dimension SDS-PAGE the proteins were fluorescently stained and the images collected by densitometry. 182 proteins differed by 2-fold between cases and controls. 141 showed lower expression in alcoholics, 33 higher, and 8 were new or had disappeared. To date 63 proteins have been identified using MALDI-MS and MS-MS. Western blots were performed on uncentrifuged individual samples from 76 subjects (controls, uncomplicated alcoholics and cirrhotic alcoholics). A common standard was run on every gel. After transfer, immunolabeling, and densitometry, the intensities of the unknown bands were compared to those of the standards. We focused on proteins from transcripts that showed clear differences in a series of microarray studies, classified into common sets including Regulators of G-protein Signaling and Myelin-associated proteins. The preponderantly lower level of differentially expressed proteins in alcoholics parallels the microarray mRNA analysis in the same samples. We found that mRNA and protein expression do not frequently correspond; this may help identify pathogenic processes acting at the level of transcription, translation, or post-translationally.

Future Engineers Australia Management Project: Turning high school students into engineering entrepreneurs

There has been a strong move towards entrepreneurial education in high schools and at universities over the past few years. This has been echoed by a call from state governments around Australia to promote enterprise thinking and education in high schools. It also parallels the push within engineering to learn across the traditional boundaries , particularly between engineering and business. To meet this call, The Engineering Link Group (TELG) developed the Future Engineers Australia Management Project (FEAMP) in 2003. The project is based around Enterprise Education, and was inspired by the Smallpeice Year 12 Engineering Management course in the UK. The idea was to take high school students in years 11 and 12 and turn them into ‘engineering entrepreneurs’. This paper presents the design, development and evaluation of FEAMP as a five day residential course for year 11 and 12 students who want to learn more about being entrepreneurs and managers. It is a hands-on activity where the students invent, develop and sell an engineering concept to venture capitalists and ultimately to customers at a trade fair. It has been run successfully for two years, going from strength to strength. © 2005, Australasian Association for Engineering Education

Reweaving the Silk Road through outsourcing and offshoring: The need for an externalisation theory

The reweaving and repaving of the modern Silk Road passes through outsourcing and offshoring activities that have a profound impact on both global business psyche and landscape. Firms, in particular, and their global value chain are being shaped and reshaped through a complex concoction of vertical integration and disintegration. The boundary of the firm and the firm/market interface has been of interest to students of organisation and economics for some time. It has provided the context for Internalisation Theory. Within the new economy, the twin trends of globalisation and advancing technologies are giving rise to a hitherto unknown “worldwide market for market transactions? and increased opportunities for international expansion by firms via market-based modes of organisation. We describe these trends and offer an early modeling approach for explaining why some firm’s externalise the marginal transaction in the so-called new economy. The paper further draws attention on the need to articulate an “Externalisation Theory? that adequately accounts for the firm’s offshoring and outsourcing activities, and that parallels as well as complement “Internalisation Theory? for a full explanation of today’s firms behaviour.

O IMAGINÁRIO DO TEMPLO CELESTE E O ATO SIMBÓLICO DE JESUS EM JERUSALÉM (MC 11:15-19): A VARIAÇÃO DE ESCALAS NA BUSCA PELO JESUS HISTÓRICO

A dissertação tem como proposta um intercâmbio entre a Nova História Cultural e a Pesquisa pelo Jesus Histórico. Os problemas colocados à historiografia atual pela pósmodernidade, a questão da subjetividade nos processos epistemológicos de construção histórica e a necessidade de reconhecimento da complexidade das ações sociais, pedem por uma metodologia que encontre uma saída à contraposição entre racionalismo e irracionalismo, entre o positivismo e a recusa em interpretar os objetos históricos. O projeto propõe a Micro- história italiana como tentativa de superar estas quimeras. A busca pelo Jesus de Nazaré funcionará assim não a partir de esquemas teóricos ge rais as estruturas permanentes do Mediterrâneo, o common judaism , ou o ethos da Baixa Galiléia mas pelo estudo fino, detalhado de um microfenômeno bastante representativo de Jesus, a sua demonstração simbólica no Templo narrada em Mc 11:15-19 e paralelos. A microanálise tratará de controlar a multiplicação da grande teia de relações causais da ação simbólica em Jerusalém e inferirá a partir delas que tipo de religioso foi Jesus e como se relacionou ao grande centro religioso do Santuário de Herodes. A variação entre as escalas microscópicas e macroscópicas de observação será também fundamental na construção das imagens plausíveis de Jesus. Inferências sobre o contexto cultural e religioso da Galiléia também serão experimentadas a partir da microação analisada o corolário de que os indivíduos são, de uma forma ou de outra, representativos de períodos históricos e de estratos culturais será levado bastante a sério. A hipótese do presente trabalho é a de que a demonstração de Jesus no Templo, longe de uma tentativa de purificação, fora a atualização de um estrutura mítica centrada em Jeremias 7 (uma mitopráxis) orientada pelo imaginário plurissecular do céu-templo, abundante nas imagens literárias da apocalíptica e no misticismo incipiente que culminará na literatura Hekhalot. Como experimento final, propor-se-á uma conexão entre supostas experiências visionárias de ascensão aos céus de Jesus de Nazaré e o seu imaginário do céu-templo.

AS MALDIÇÕES DO SALMO 137: O princípio da reciprocidade na justiça do Antigo Testamento como chave bíblica para a interpretação

Esta tese, baseada na exegese, defende que as maldições do Salmo 137 devem ser interpretadas levando-se em conta o princípio da reciprocidade praticado na justiça do AT, o famoso "olho por olho, dente por dente". Apresenta auxílios para a interpretação das maldições nos salmos; analisa o estado atual da questão; verifica a coerência ou não da utilização do termo "Salmo Imprecatório"; trata da difícil questão do contexto histórico dos salmos e, ainda, destaca alguns pontos que dificultam a interpretação cristã deste tipo de literatura. Ela trata das questões do texto, da estrutura, do gênero literário, da autoria, e do contexto de vida e histórico do Salmo 137. Além disso, apresenta paralelos deste gênero no mundo bíblico e compara versões do Salmo 137 em português. Mostra que no AT a palavra era tratada como algo que possui poder intrinseco; verifica como, normalmente, era feito o uso das maldições no AT em geral, preparando o caminho para a verificação de seu uso específico no Salmo 137; faz uma rápida retrospectiva histórica mostrando a longa trajetória de desavenças de Israel/Judá com Edom e Babilônia, o que leva o salmista a sentir-se no direito de pedir que estas duas nações sejam destruídas e sofram; levanta, ainda, a possibilidade do Salmo 137 não ser o único do Saltério com maldições contra Edom e Babilônia, e destaca que nesta composição existe uma automaldição e duas maldições, uma contra Edom e outra contra Babilônia, todas elas levando em conta o princípio da reciprocidade na justiça do AT.(AU)

Quem é Este? Poder, Medo e Identidade Mítica na Narrativa de Marcos 4. 35 41

Esta dissertação elabora uma exegese de Marcos 4. 35 41, Jesus Acalma uma Tempestade . Para tanto, parte da revisão crítica da pesquisa atual do Jesus Histórico em diálogo com a História Cultural, Micro-história e Psicologia Histórica, com o intuito de levantar questões pertinentes às narrativas míticas e sua importância para o saber histórico. Do mapeamento literário dos Papiros Mágicos Gregos, bem como referência ao Hino de Auto-Exaltação de Qumran, ao antigo testamento e a textos rabínicos posteriores ao Novo Testamento, emergem paralelos que são fundamentais para a compreensão da perícope analisada. Assim, a exegese do texto em questão lança luz sobre os elementos de poder, medo e identidade mítica presentes na narrativa.(AU)

"Patrie et Humanité" (1928):Politique et relations internationales

One fundamental question raised by the philosophical works of Maurice Blondel, which were published over a long life, is that of the relation between his early masterpiece L’Action (1893) and the volume of the same name—more precisely, its second tome L’Action humaine et les conditions de son aboutissement (1937)—forming part of the Trilogy of his later years (La Pensée; L’Être et les êtres; L’Action). The treatment of the nature of international relations in the work of 1937 is more developed than that found in L’Action of 1893. For understanding the development of Blondel’s thought on this matter, the key text is "Patrie et Humanité", a paper prepared for the 1928 annual meeting, held in Paris, of the Catholic Semaine sociale movement. It brings out the affinity between his understanding of international relations and that represented by such established thinkers in the canon of international thought as Vitoria and Suarez (in the case of the latter, despite some radical difference in respect of metaphysics). Not surprisingly from the standpoint of the genesis of Blondel’s philosophy, there is also a certain affinity between his view of the importance of justice for international affairs and that of Leibniz (notably in the preface of the Codex Juris Gentium, 1693). Various specialists treating of Blondel’s philosophy have drawn attention to parallels between the phenomenology of the will in L’Action of 1893 and Hegel’s Phänomenologie des Geistes. However, as regards the two philosophers’ understanding of the nature of international relations, there is a considerable gulf, and some of the difference may be related to the Hegelian idea of the Christian Church as found, at least implicitly, in the Grundlinien der Philosophie des Rechts (1821).

Depth propagation and surface construction in 3-D vision

Motion discontinuities can signal object boundaries where few or no other cues, such as luminance, colour, or texture, are available. Hence, motion-defined contours are an ecologically important counterpart to luminance contours. We developed a novel motion-defined Gabor stimulus to investigate the nature of neural operators analysing visual motion fields in order to draw parallels with known luminance operators. Luminance-defined Gabors have been successfully used to discern the spatial-extent and spatial-frequency specificity of possible visual contour detectors. We now extend these studies into the motion domain. We define a stimulus using limited-lifetime moving dots whose velocity is described over 2-D space by a Gabor pattern surrounded by randomly moving dots. Participants were asked to determine whether the orientation of the Gabor pattern (and hence of the motion contours) was vertical or horizontal in a 2AFC task, and the proportion of correct responses was recorded. We found that with practice participants became highly proficient at this task, able in certain cases to reach 90% accuracy with only 12 limited-lifetime dots. However, for both practised and novice participants we found that the ability to detect a single boundary saturates with the size of the Gaussian envelope of the Gabor at approximately 5 deg full-width at half-height. At this optimal size we then varied spatial frequency and found the optimum was at the lowest measured spatial frequency (0.1 cycle deg-1 ) and then steadily decreased with higher spatial frequencies, suggesting that motion contour detectors may be specifically tuned to a single, isolated edge.

Molecularly imprinted polymers in the drug discovery process

Since molecularly imprinted polymers (MIPs) are designed to have a memory for their molecular templates it is easy to draw parallels with the affinity between biological receptors and their substrates. Could MIPs take the place of natural receptors in the selection of potential drug molecules from synthetic compound libraries? To answer that question this review discusses the results of MIP studies which attempt to emulate natural receptors. In addition the possible use of MIPs to guide a compound library synthesis towards a desired biological activity is highlighted. © 2005 Elsevier B.V. All rights reserved.

Disordered connectivity in the autistic brain:challenges for the 'new psychophysiology'

In 2002, we published a paper [Brock, J., Brown, C., Boucher, J., Rippon, G., 2002. The temporal binding deficit hypothesis of autism. Development and Psychopathology 142, 209-224] highlighting the parallels between the psychological model of 'central coherence' in information processing [Frith, U., 1989. Autism: Explaining the Enigma. Blackwell, Oxford] and the neuroscience model of neural integration or 'temporal binding'. We proposed that autism is associated with abnormalities of information integration that is caused by a reduction in the connectivity between specialised local neural networks in the brain and possible overconnectivity within the isolated individual neural assemblies. The current paper updates this model, providing a summary of theoretical and empirical advances in research implicating disordered connectivity in autism. This is in the context of changes in the approach to the core psychological deficits in autism, of greater emphasis on 'interactive specialisation' and the resultant stress on early and/or low-level deficits and their cascading effects on the developing brain [Johnson, M.H., Halit, H., Grice, S.J., Karmiloff-Smith, A., 2002. Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis. Development and Psychopathology 14, 521-536].We also highlight recent developments in the measurement and modelling of connectivity, particularly in the emerging ability to track the temporal dynamics of the brain using electroencephalography (EEG) and magnetoencephalography (MEG) and to investigate the signal characteristics of this activity. This advance could be particularly pertinent in testing an emerging model of effective connectivity based on the balance between excitatory and inhibitory cortical activity [Rubenstein, J.L., Merzenich M.M., 2003. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior 2, 255-267; Brown, C., Gruber, T., Rippon, G., Brock, J., Boucher, J., 2005. Gamma abnormalities during perception of illusory figures in autism. Cortex 41, 364-376]. Finally, we note that the consequence of this convergence of research developments not only enables a greater understanding of autism but also has implications for prevention and remediation. © 2006.

The advanced learner variety:the case of French

This volume originates from a workshop entitled 'Revisiting advanced varieties in L2 learning' organized by the editors at Aston University (Birmingham, UK) in June 2006. It consists of a peer-reviewed selection of the best contributions. Many different approaches have been used in the study of advanced learners and their characteristics. Specific areas of language have repeatedly been found to remain problematic even at advanced levels, and much empirical research has been carried out. In particular, areas of grammar such as the tense or agreement systems often pose difficulties, as well as lexical idiosyncrasies such as formulaic sequences, and the discourse/pragmatic constraints operating in French. This volume brings together recent research exploring the advanced learner capabilities in each of those domains, as well as possible explanations for the difficulties they raise for the L2 learner of French. Additionally, one of the areas which has received considerable attention in the French L2 literature on advanced learners, tense and aspect, is also explored from the point of view of French learners of English, to explore any parallels. In presenting this research, the book clarifies the concept of the advanced learner: how does s/he differ from native speakers and why?

An investigation into the pharmacology of tics and tic-like movements

The study of tic-like movements in mice has demonstrated close parallels both in characteristics and in pharmacology with the tics which occur in TS. Head-shakes and/or other tic-like behaviours occurring spontaneously or induced by the selective 5-HT2/1C agonist DOI, alpha-melanocyte stimulating hormone, adrenocorticotrophic hormone (1-39), thyrotropin releasing hormone, or RX336-M were blocked when tested with neuroleptics such as haloperidol and/or the alpha-2 adrenoceptor agonist clonidine. The selective dopamine D1 antagonists SCH23390 and SCH39166 dose-dependently blocked spontaneous and DOI head-shakes but the selective dopamine D2 antagonists sulpiride and raclopride were ineffective. The 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone, gepirone, MDL 73005EF and buspirone (i.p) dose-dependently blocked DOI head-shakes, pindolol blocked the inhibitory effect of 8-OH-DPAT on DOI head-shakes. Parachlorophenylalanine blocked the inhibitory effect of 8-OH-DPAT and buspirone, suggesting that the 5-HT1A receptor involved is located presynaptically. The alpha-2 adrenoceptor antagonists yohimbine, idazoxan, 1-PP and RX811059 prevented the inhibitory effect of 8-OH-DPAT on DOI head-shakes suggesting that this 5-HT1A - 5-HT2 receptor interaction is under the modulatory control of adrenoceptors. Because kynurenine has previously been found to potentiate head-shaking, plasma kynurenine concentrations were measured in seven TS patients and were significantly higher than controls, but neopterin and biopterin were unchanged. The relationship between tic-like movements in rodents and their implications for understanding the aetiology and treatment of TS is discussed.

Infraslow (<0.1 Hz) oscillations in thalamic relay nuclei basic mechanisms and significance to health and disease states

In the absence of external stimuli, the mammalian brain continues to display a rich variety of spontaneous activity. Such activity is often highly stereotypical, is invariably rhythmic, and can occur with periodicities ranging from a few milliseconds to several minutes. Recently, there has been a particular resurgence of interest in fluctuations in brain activity occurring at <0.1 Hz, commonly referred to as very slow or infraslow oscillations (ISOs). Whilst this is primarily due to the emergence of functional magnetic resonance imaging (fMRI) as a technique which has revolutionized the study of human brain dynamics, it is also a consequence of the application of full band electroencephalography (fbEEG). Despite these technical advances, the precise mechanisms which lead to ISOs in the brain remain unclear. In a host of animal studies, one brain region that consistently shows oscillations at <0.1 Hz is the thalamus. Importantly, similar oscillations can also be observed in slices of isolated thalamic relay nuclei maintained in vitro. Here, we discuss the nature and mechanisms of these oscillations, paying particular attention to a potential role for astrocytes in their genesis. We also highlight the relationship between this activity and ongoing local network oscillations in the alpha (a; ~8-13 Hz) band, drawing clear parallels with observations made in vivo. Last, we consider the relevance of these thalamic ISOs to the pathological activity that occurs in certain types of epilepsy.

Distinctive manufacturing competence or core competence:which is more relevant in non-corporate organizations?

This paper addresses the issues of what core competencies mean in the light of the earlier existing concept of distinctive manufacturing competencies (or manufacturing competencies). The apparent parallels bel ween these two concepts are highlighted and considered. The results of empirical research comlucled via a survey of UK non-corporate organizations is presented and then analyzed. The results from the investigation lead directly to conclusions about the relevance of these competency concepts to non-corporate, non-multinational organizations.

Linking comprehensive performance assessment to the balanced scorecard:evidence from Hertfordshire County Council

Over the course of the last twenty years there has been a growing academic interest in performance management, particularly in respect of the evolution of new techniques and their resulting impact. One important theoretical development has been the emergence of multidimensional performance measurement models that are potentially applicable within the public sector. Empirically, academic researchers are increasingly supporting the use of such models as a way of improving public sector management and the effectiveness of service provision (Mayston, 1985; Pollitt, 1986; Bates and Brignall, 1993; and Massey, 1999). This paper seeks to add to the literature by using both theoretical and empirical evidence to argue that CPA, the external inspection tool used by the Audit Commission to evaluate local authority performance management, is a version of the Balanced Scorecard which, when adapted for internal use, may have beneficial effects. After demonstrating the parallels between the CPA framework and Kaplan and Norton's public sector Balanced Scorecard (BSC), we use a case study of the BSC based performance management system in Hertfordshire County Council to demonstrate the empirical linkages between a local scorecard and CPA. We conclude that CPA is based upon the BSC and has the potential to serve as a springboard for the evolution of local authority performance management systems.