bluuebunny/crossref_metadata_2025 huggingface dataset:
Data Availability and Maintenance Planning in Less Developed Countries
Authors: Fekpe Edward S. K.
Published: March 2008

Abstract: The need, relevance and advantages of effective data base management in road maintenance planning; and the impact of data inadequacies on evaluation of road maintenance alternative strategies are presented.

The problem of poor data base development and management in less developed countries may be due to financial, institutional and technical considerations. A properly developed and managed data base will facilitate the establishment of relationships and models necessary to understand and predict performance of highway infrastructure. This is to enhance efficient allocation of scarce resources to maintenance and rehabilitation.

Grouping road links of similar traffic and pavement structural characteristics into categories is demonstrated as an efficient means of coarse evaluation of road network at regional or national levels. Depending on the structural integrity of the pavement, as measured by the structural number, the input parameters have different levels of impact in determining the best maintenance alternative. Lack of or inaccurate data may yield misleading result leading to inefficient allocation of scarce resources. The importance of a well managed data base in achieving cost‐effectiveness in road maintenance planning is highlighted.

Résumé: Cet article porte sur la nécessité, l'utilité et les avantages d'une gestion efficace d'une banque de données sur la planification de la maintenance des routes; et l'incidence de données insuffisantes sur l'évaluation des stratégies alternatives de maintenance des routes.

Des facteurs financiers, institutionnels et techniques sont peut‐étre à l'origine de la médiocrité de la mise en valeur et de la gestion des banques de données dans les pays en développement. Une banque de données bien conçue, et gérée correctement, devrait faciliter la création des relations et des modèles nécessaires à la compréhension et à la prévision de la performance de l'infrastructure des autoroutes. Elle devrait favoriser une allocation efficace des maigres ressources destinées à la maintenance et à la réhabilitation.

Il a été prouvé que le regroupement par catégories, des liaisons routières dont le trafic et la structure de la chaussée présentent des caractéristiques similaires, est un moyen efficace d'évaluer sommairement l'état des réseaux routiers régionaux et nationaux. En fonction de l'intégrité structurale de la chaussée, qui est déterminée par le nombre de couches de cette chaussée, les paramètres des intrants ont un impact différent sur le choix de la maintenance la plus indiquée. Des données insuffisantes ou inexactes peuvent se traduire par des résultats érronés, ce qui va entraîner une affectation inefficace des maigres ressources. L'article souligne l'importance d'une banque de données bien gérée pour réaliser une planification rentable de la maintenance des routes.
The Parameters of Science and Technology Policy Formulation in South Africa
Authors: Scerri Mario
Published: March 2008

Abstract:This paper examines the history of Science and Technology policy in South Africa over the period starting in 1916, when the first national initiative in this field was launched, and ending in 1996 which saw the tabling of the country's first White Paper on Science and Technology. The main argument of this paper is that, in spite of the dramatic changes in the country's political and economic history from segregation through apartheid and finally to its first democratic government, there exists a strong commonality in the structural context within which Science and Technology policy has been formulated. Consequently, it will be argued, the limitations on the scope of planning in this field have remained essentially unchanged resulting in a disturbing similarity between the pre‐ and the post‐apartheid visions of the role of the state in this area of public policy.

L'auteur de cet article examine Fhistoire de la politique relative à la science et à la technologie en Afrique du Sud de 1916, date de la premiére initiative nationale dans ce domaine, à 1996, date de présentation du premier Livre blanc sur la science et la technologie. Le principal argument développé dans cet article est qu'en dépit de changements radicaux intervenus dans l'histoire politique et économique du pays, de la péiode d'apartheid au premier gouvernement démocratique, il y a une forte similitude du contexte structurel dans lequel la politique relative à la science et à la technologie a été formulée. En conséquence, conclut l'auteur, les restrictions quant á l'envergure de la planification dans ce domaine sont restées essentiellement intactes, donnant lieu à une similitude gênante entre les perceptions avant et post‐apartheid du rôle de l'Etat en matière de politique publique.
Towards the Development of an Equitable African Information Society
Authors: Fouché Ben
Published: March 2008

Abstract:The ongoing global information and communications revolution, based on the convergence of information and communication technologies (ICTs) and the digitalisation of information, has brought about a new post industrial economic and societal world order, the so called global information economy and society. This represents tremendous challenges and opportunities, but also threats, to which African countries must respond.

Industrialised countries and emerging economies around the world are giving high priority to the development of national and regional information infrastructures and strategies to develop internationally competitive Information Societies. This is considered to be necessary for effective participation in the global knowledge based economy.

The article reviews recent developments pertaining to the application of ICTs in support of social development and economic growth in Africa. Factors which affect the development of an equitable Information Society in Africa are analysed with reference to experience elsewhere. Finally, some conclusions are drawn about technology management and human capacity strategies for African countries.

La révolution mondiale actuelle de l'information et de la communication, fondée sur la convergence des technologies de l'information et de la communication et la numérisation de l'information, a débouché sur un nouvel ordre économique et social postindustriel, dit économie et société mondiales de l'information. Cela représente des défis exaltants et des opportunités, mais aussi des risques pour les pays africains.

Les pays industrialisés et les économies émergentes de par le monde, accordent une haute priorité au développement des infrastructures et stratégies nationales et régionales qui leur permettraient de bâtir des sociétés d'information compétitives à l'échelon international. Cela paraît nécessaire pour une participation effective à l'économie fondée sur la connaissance mondiale.

L'auteur du présent article examine l'évolution récente liée à l'application des technologies de l'information et de la communication à l'appui du développement social et de la croissance économique en Afrique. Les facteurs qui influencent l'avènement d'une société d'information équitable en Afrique sont analysés en fonction de l'expérience acquise ailleurs dans le monde. Enfin, l'auteur tire certaines conclusions sur la gestion des technologies et les stratégies de valorisation des ressources humaines pour les pays africains.
Les Politiques de Restructuration de l'Economie Camerounaise: Evaluation Rétrospective à Moyen‐Terme
Authors: ATEBA Etienne Modeste ASSIGA
Published: March 2008

Abstract: In this article, we assess the medium‐term impact of Cameroon's economic restructuring policies, after about one decade of their application (1987–1997). More specifically, we analyze, according to the logic underlying the preparation of reform programmes, the reduction of internal and external deficits in the short‐term, through stabilization measures; and the correction of distortions on the prices of products and factors in the medium‐term, through structural adjustment programmes. The results indicate that joint stabilization and structural adjustment programmes seem to be, in the medium‐term, the cause of the reversal of the trend towards deterioration of certain macroeconomic indicators such as real growth rate and internal and external deficits. On the other hand, the social impacts of these policies have been insignificant, and they continue to weigh heavily on public finance. A persistent and exponential growth of the unemployment rate and rapid informalization of the economy can be noticed.

Dans cet article, nous évaluons l'impact à moyen terme, des politiques de restructuration de l'économie camerounaise, après environ une décennie de leur mise en application (1987–1997). Plus spécifiquement, nous analysons, selon la logique qui sous‐tend l'élaboration des programmes de réformes, la résorption des déficits internes et externes à travers les politiques de stabilisation à court terme et la correction des distorsions sur les prix des produits et des facteurs, cette fois‐ci, à moyen terme, à travers les programmes d'ajustement structurel. Les résultats indiquent que les politiques conjointes de stabilisation et d'ajustement structurel semblent être, à moyen terme, à l'origine du renversement de tendance à la détérioration des certains indicateurs macro‐économiques tels que le taux de croissance réel et les déficits internes et externes. Par contre, les effets sociaux de ces politiques ont été peu significatifs, et elles continuent à peser lourd sur les finances publiques. L'on constate une croissance persistante et exponentielle du taux de chômage et une informalisation rapide de l'économie.
Why Adopt Codes of Good Governance? A Comparison of Institutional and Efficiency Perspectives
Authors: Zattoni Alessandro , Cuomo Francesca
Published: March 2008

Manuscript Type:Empirical

Research Question/Issue:Given the global diffusion and the relevance of codes of good governance, the aim of this article is to investigate if the main reason behind their proliferation in civil law countries is: (i) the determination to improve the efficiency of the national governance system; or (ii) the will to “legitimize” domestic companies in the global financial market without radically improving the governance practices.

Research Findings/Insights:We collected corporate governance codes developed worldwide at the end of 2005, and classified them according to the country's legal system (common or civil law). Then, we made a comparative analysis of the scope, coverage, and strictness of recommendations of the codes. We tested differences between common law and civil law countries using t‐tests and probit models. Our findings suggest that the issuance of codes in civil law countries be prompted more by legitimation reasons than by the determination to improve the governance practices of national companies.

Theoretical/Academic Implications:The study contributes to enriching our knowledge on the process of reinvention characterizing the diffusion of new practices. Our results are consistent with a symbolic perspective on corporate governance, and support the view that diffusing practices are usually modified or “reinvented” by adopters.

Practitioner/Policy Implications:Our results support the idea that the characteristics of the national corporate governance system and law explain the main differences among the coverage of codes. This conclusion indicates the existence of a strong interplay between hard and soft law.
Stored Word Sequences in Language Learning
Authors: Bannard Colin , Matthews Danielle
Published: March 2008

Recent accounts of the development of grammar propose that children remember utterances they hear and draw generalizations over these stored exemplars. This study tested these accounts' assumption that children store utterances as wholes by testing memory for familiar sequences of words. Using a newly available, dense corpus of child-directed speech, we identified frequently occurring chunks in the input (e.g., sit in your chair) and matched them to infrequent sequences (e.g., sit in your truck). We tested young children's ability to produce these sequences in a sentence-repetition test. Three-year-olds (n = 21) and 2-year-olds (n = 17) were significantly more likely to repeat frequent sequences correctly than to repeat infrequent sequences correctly. Moreover, the 3-year-olds were significantly faster to repeat the first three words of an item if they formed part of a chunk (e.g., they were quicker to say sit in your when the following word was chair than when it was truck). We discuss the implications of these results for theories of language development and processing.
Nonconscious Goal Pursuit in Novel Environments
Authors: Eitam Baruch , Hassin Ran R. , Schul Yaacov
Published: March 2008

Is nonconscious goal pursuit useful in novel environments? The prevalent view of automaticity and control implies that an unconscious mode of goal pursuit can only reproduce formerly learned actions, and therefore that its usefulness in novel environments is very limited. Our results demonstrate that this conclusion is not always warranted, as nonconscious goal pursuit facilitated participants' learning of the structure of completely novel environments. Specifically, two experiments, using markedly different implicit-learning paradigms, demonstrated facilitation of implicit learning when the goal of achievement was primed. We propose that nonconscious goal pursuit can facilitate not only reproductive operations, but also productive ones, and that implicit learning is sensitive to the organism's nonconscious goals.
Emotional Valence and Arousal Interact in Attentional Control
Authors: Jefferies Lisa N. , Smilek Daniel , Eich Eric , Enns James T.
Published: March 2008

A recent study demonstrated that observers' ability to identify targets in a rapid visual sequence was enhanced when they simultaneously listened to happy music. In the study reported here, we examined how the emotion-attention relationship is influenced by changes in both mood valence (negative vs. positive) and arousal (low vs. high). We used a standard induction procedure to generate calm, happy, sad, and anxious moods in participants. Results for an attentional blink task showed no differences in first-target accuracy, but second-target accuracy was highest for participants with low arousal and negative affect (sad), lowest for those with strong arousal and negative affect (anxious), and intermediate for those with positive affect regardless of their arousal (calm, happy). We discuss implications of this valence-arousal interaction for the control of visual attention.
Night and Day, You Are the One
Authors: Kruglanski Arie W. , Pierro Antonio
Published: March 2008

A study examined the relation between individuals' circadian rhythm and their tendency to exhibit transference effects in social perception. Individuals tested at times of circadian mismatch (i.e., morning persons tested in the evening and evening persons tested in the morning) exhibited more pronounced transference effects than individuals tested at times of circadian match (i.e., morning persons tested in the morning and evening persons tested in the evening). These findings are compatible with the notion that transference effects represent everyday social-cognitive functioning related to activation of social schemata. Additionally, however, they suggest that transference effects are not the inevitable consequence of activating the significant other's schema. Rather, such effects might be particularly likely to occur when an individual's mental resources are limited, as might be the case during circadian mismatches. This latter suggestion differs from psychodynamic views of transference as exclusively a driven, energy-intensive phenomenon.
PERFORMING AUTHORITY: DISCURSIVE POLITICS AFTER THE ASSASSINATION OF THEO VAN GOGH
Authors: HAJER MAARTEN , UITERMARK JUSTUS
Published: March 2008

In November 2004, the assassination of the filmmaker Theo van Gogh in Amsterdam by an Islamic extremist shocked The Netherlands. Critics of multiculturalism quickly linked the murder to the perceived failure of ‘soft’ integration policies and questioned the authority and legitimacy of Amsterdam’s political leadership. This article studies the response of political leaders to those challenges from a performative perspective. Analysing governance as performance illuminates the importance of actively enacting political leadership in non‐parliamentary settings such as talk shows, mosques and other religious meeting places, and improvised mass meetings in times of crisis. The authors distinguish different discursive means of performing authority, make suggestions for dealing with crisis events in ethnically and culturally diverse cities and draw some lessons from this approach as well as for methods of studying public administration.
QUEER(Y)ING PUBLIC ADMINISTRATION
Authors: LEE HUGH , LEARMONTH MARK , HARDING NANCY
Published: March 2008

Queer theory, understood here as a set of political/politicized practices and positions which resist normative knowledge and identities, has emerged as a theoretical perspective having important emancipatory and explanatory power in the arts, humanities and social sciences. Queer theory resists definitionipso facto, residing as it does within a postructuralist paradigm. It has not hitherto featured within the discipline of public administration and we argue the case for its utilisation in this field by first explicating the theory. Here we develop a way of using queer theory to analyse data, notably through the identification of the ‘moments’ of a queer theory analysis: identification of the norms that govern identity, analysis of what is allowable within those norms, and exploration of what is unspeakable. We demonstrate its use via an empirically‐based case study. The lessons from this exercise are then applied to some of our earlier work which we re‐read through a queer theory lens. This shows the great explanatory power offered by the theory, in that it can develop insights that previously have been inaccessible. We conclude with recommendations for its broader application and wider use within public administration.
The IMF and the Liberalization of Capital Flows
Authors: Joyce Joseph P. , Noy Ilan
Published: March 2008

We evaluate the claim that the International Monetary Fund precipitated financial crises during the 1990s, by pressuring countries to liberalize their capital accounts prematurely. Using data from a panel of developing economies from 1982–98, we examine whether the changes in the regime governing capital flows took place during participation in IMF programs. We find evidence that IMF program participation is correlated with capital account liberalization episodes during the 1990s. We verify the robustness of our results using alternative indicators of capital account openness. To determine whether decontrol was premature, we compare the economic and financial characteristics of countries that decontrolled during IMF programs with those of countries who did so independently, and find some evidence of IMF‐led premature liberalizations.
Dynamic Patterns of Trade Imbalances with Recursive Preference
Authors: Inoue Tadashi
Published: March 2008

Based on the recursive preference approach, the dynamic and global properties of the two‐country open economy are examined with one good and inputs of labor and capital, with capital being freely traded internationally. First, by showing that the world's consumption increases (decreases) with an increase (decrease) in the world's capital, the global stability of the economy is obtained. Secondly, the nonmonotonicity of consumption between impatient country 1 and patient country 2 is established. Thirdly, with the Cobb–Douglas‐type production function and country 1's technological superiority, the dynamic trade patterns and the asset–debt position are derived.
Democracy and State Capacity: Exploring a J‐Shaped Relationship
Authors: BÄCK HANNA , HADENIUS AXEL
Published: March 2008

In this article we probe the effect of democratization on the state's administrative capacity. Using time‐series cross‐section data, we find a curvilinear (J‐shaped) relationship between the two traits. The effect of democracy on state capacity is negative at low values of democracy, nonexistent at median values, and strongly positive at high democracy levels. This is confirmed under demanding statistical tests. The curvilinear relationship is due, we argue, to the combined effect of two forms of steering and control; one exercised from above, the other from below. In strongly authoritarian states, a satisfactory measure of control from above can at times be accomplished. Control from below is best achieved when democratic institutions are fully installed and are accompanied by a broad array of societal resources. Looking at two resource measures, press circulation and electoral participation, we find that these, combined with democracy, enhance state administrative capacity.
Fair Treatment in a Divided Society: A Bottom‐up Assessment of Bureaucratic Encounters in Latvia
Authors: GALBREATH DAVID J. , ROSE RICHARD
Published: March 2008

In real‐world bureaucratic encounters the Weberian goal of perfect impersonal administration is not completely attained and unfairness sometimes results. Theories of bias attribute unfairness to social characteristics such as income, education, ethnicity, and gender. A random theory characterizes unfairness as the result of idiosyncratic conditions that give everyone an equal probability of being treated unfairly regardless of their social characteristics. In Latvia, bias would be expected on grounds of ethnicity as well as social characteristics, since its population is divided politically by citizenship, language, and ethnicity as well as socioeconomic characteristics. Survey data from the New Baltic Barometer shows that a majority of both Latvians and Russians expect fair treatment in bureaucratic encounters and multivariate statistical analysis confirms the random hypothesis. Insofar as unfair treatment occurs it tends to be distributed according to idiosyncratic circumstances rather than being the systematic fate of members of a particular social group. The evidence indicates that the professional norms and training of service deliverers are more important in bureaucratic encounters than individual attributes of claimants, even in a clearly divided society.
ALS patients request more information about cognitive symptoms
Authors: Wicks P. , Frost J.
Published: March 2008

Background and purpose:  Once thought to impact only voluntary motor function, ALS/Motor neuron disease (MND) is now seen as a multi‐system disorder in which a minority of patients experience mild cognitive dysfunction or frontotemporal dementia. Despite clinical guidelines advocating supplying complete information to patients, educational materials on ALS often state that the mind is unaffected. We sought to establish how much patients and caregivers understand about ALS, what they have been told to expect by their physician, and if they would have appreciated more complete information.

Methods:  A two‐part survey was administered online. An ‘ALS quiz’ gauged participants’ knowledge of physical and psychological aspects of ALS. A second questionnaire assessed which symptoms patients had discussed with their clinician and explored patients’ desire to receive information on psychological effects.

Results:  A total of 247 ALS patients and 87 caregivers participated. Participants knew less about psychological symptoms than physical ones (72% correct responses versus 82%; paired t(333) = −5.04, P < 0.001). Patients commonly reported being told by their doctor about physical symptoms such as problems walking (85%) or stiffness/cramps (74%) but not psychological issues like emotional lability (46%) or cognitive change (11%). The majority of patients (62%) and carers (71%) indicated a desire to be informed that cognitive change or dementia might occur.

Conclusion:  ALS is a multi‐system disorder. However, despite a desire for more information from patients and their carers, healthcare professionals continue to primarily address only the physical consequences of the disease.
Insider Trading and Earnings Management
Authors: Sawicki Julia , Shrestha Keshab
Published: March 2008

Abstract:  This paper analyzes the relationship between earnings management and insider trading, specifically investigating whether discretionary accruals are related to insider trading and valuation. We find strong evidence of insiders managing earnings downward when buying and managing earnings upward when selling. On the marginal basis, value (high book‐to‐market value) firms manage their earnings upward compared to growth (low book‐to‐market value) firms, consistent with a signaling hypothesis. However, the opposite is true on the average basis, consistent with an opportunistic hypothesis.
Information Asymmetry and Bidders' Gains
Authors: Draper Paul , Paudyal Krishna
Published: March 2008

Abstract:  Undervalued firms with high information asymmetry may announce takeover bids to attract the attention of investors with a view to increasing the share price through revaluation. Announcement period returns to such bidders should include both revaluation and synergy gains although the revaluation gains should be confined to early bids and decline with the number of bids announced within a reasonable period. Our results offer strong support to these predictions. Undervalued firms with high pre‐bid information asymmetry gain the most from early bids and the gains decline with the number of bids announced. These findings are robust to methods of payment, relative size of deals, target status, relatedness of businesses, domicile of target, M&A activities and alternative measures of information asymmetry, and confirm that gains from early bids include revaluation as well as synergy gains, especially in the cases of undervalued firms with high information asymmetry.
Activity‐dependent heteromerization of the hyperpolarization‐activated, cyclic‐nucleotide gated (HCN) channels: role of N‐linked glycosylation
Authors: Zha Qinqin , Brewster Amy L. , Richichi Cristina , Bender Roland A. , Baram Tallie Z.
Published: March 2008

Formation of heteromeric complexes of ion channels via co‐assembly of different subunit isoforms provides an important mechanism for enhanced channel diversity. We have previously demonstrated co‐association of the hyperpolarization activated cyclic‐nucleotide gated (HCN1/HCN2) channel isoforms that was regulated by network (seizure) activity in developing hippocampus. However, the mechanisms that underlie this augmented expression of heteromeric complexes have remained unknown. Glycosylation of the HCN channels has been implicated in the stabilization and membrane expression of heteromeric HCN1/HCN2 constructs in heterologous systems. Therefore, we used in vivo and in vitro systems to test the hypothesis that activity modifies HCN1/HCN2 heteromerization in neurons by modulating the glycosylation state of the channel molecules. Seizure‐like activity (SA) increased HCN1/HCN2 heteromerization in hippocampus in vivo as well as in hippocampal organotypic slice cultures. This activity increased the abundance of glycosylated HCN1 but not HCN2‐channel molecules. In addition, glycosylated HCN1 channels were preferentially co‐immunoprecipitated with the HCN2 isoforms. Provoking SA in vitro in the presence of the N‐linked glycosylation blocker tunicamycin abrogated the activity‐dependent increase of HCN1/HCN2 heteromerization. Thus, hippocampal HCN1 molecules have a significantly higher probability of being glycosylated after SA, and this might promote a stable heteromerization with HCN2.
Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine‐induced acute thermal nociception
Authors: Ghelardini Carla , Galeotti Nicoletta , Vivoli Elisa , Norcini Monica , Zhu Wei , Stefano George B. , Guarna Massimo , Bianchi Enrica
Published: March 2008

Previous evidence demonstrates that low dose morphine systemic administration induces acute thermal hyperalgesia in normal mice through μOR stimulation of the inositol signaling pathway. We investigated the site of action of morphine and the mechanism of action of μOR activation by morphine to NMDA receptor as it relates to acute thermal hyperalgesia. Our experiments show that acute thermal hyperalgesia is blocked in periaqueductal gray with the μOR antagonist CTOP, the NMDA antagonist MK801 and the protein kinase C inhibitor chelerythrine. Therefore, a site of action of systemically administered morphine low dose on acute thermal hyperalgesic response appears to be located at the periaqueductal gray. At this supraspinal site, μOR stimulation by systemically morphine low dose administration leads to an increased phosphorylation of specific subunit of NMDA receptor. Our experiments show that the phosphorylation of subunit 1 of NMDA receptor parallels the acute thermal hyperalgesia suggesting a role for this subunit in morphine‐induced hyperalgesia. Protein kinase C appears to be the key element that links μOR activation by morphine administration to mice with the recruitment of the NMDA/glutamatergic system involved in the thermal hyperalgesic response.
GSK‐3β down‐regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress
Authors: Rojo Ana I. , Sagarra María Rosa de , Cuadrado Antonio
Published: March 2008

Oxidant injury activates the neuroprotective pathway represented by phosphatidylinositol 3 kinase (PI3K) and Akt. However, the final outcome of oxidant exposure is often associated with neuronal death. This study was aimed to identify the molecular mechanism responsible for loss of tolerance to an oxidative environment. In N2A neuroblasts, serum and H2O2 exhibited different kinetics of regulation for the Ser/Thr kinases Akt and glycogen synthase kinase 3β (GSK‐3β) and for the transcription factor Nrf2, which governs redox homeostasis. Thus, H2O2 rapidly activated Akt, inhibited GSK‐3β, and directed the transcription factor Nrf2 to the nucleus, but after 4 h Akt was inactive, GSK‐3β was active and Nrf2 was more cytosolic than nuclear. Inhibition of the PI3K/Akt pathway by LY294002, impeded the short‐term effect of H2O2 on nuclear translocation of Nrf2. GSK‐3β activation (inhibiting PI3K/Akt) or direct GSK‐3β inhibition in cerebellar granule neurons resulted in respective nuclear exclusion and nuclear accumulation of Nrf2. Moreover, in these neurons, nuclear accumulation of Nrf2 correlated with increased heme oxygenase‐1 expression. Over‐expression of the kinase active GSK‐3β (Δ9) mutant, induced Nrf2 cytoplasmic localization and inhibited Nrf2 transcriptional activity towards an antioxidant‐response‐element luciferase reporter. Moreover, GSK‐3β (Δ9) sensitized N2A neuroblasts to H2O2‐induced oxidative stress and cell death. This study identifies GSK‐3β, a kinase known to participate in neurodegeneration, as a fundamental element in the down‐regulation of the antioxidant cell defense elicited by Nrf2 after oxidant injury and provides a mechanism to explain the loss of oxidant tolerance that happens under persistent oxidant exposure such as those found in several neuropathologies.
Docosahexaenoic acid prevents lipopolysaccharide‐induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization
Authors: De Smedt‐Peyrusse Véronique , Sargueil Françoise , Moranis Aurélie , Harizi Hedi , Mongrand Sébastien , Layé Sophie
Published: March 2008

Recognition of lipopolysaccharide (LPS), the endotoxin of gram‐negative bacteria, by microglia occurs through its binding to specific receptors, cluster of differentiation 14 and toll‐like receptor‐4. LPS binding to these receptors triggers the synthesis of proinflammatory cytokines that coordinate the brain innate immune response to protect the CNS of the infection. Docosahexaenoic acid (DHA), a n‐3 polyunsaturated fatty acid highly incorporated in the brain, is a potent immunomodulator. In this study, we investigated whether DHA modulates LPS receptor localization and, as a consequence, LPS‐induced signaling pathway and proinflammatory cytokine production. We demonstrated that DHA, when added exogenously, is specifically enriched in membrane phospholipids, but not in raft lipids of microglial cells. DHA incorporation in membrane impaired surface presentation of LPS receptors cluster of differentiation 14 and toll‐like receptor‐4, but not their membrane subdomain localization. LPS‐induced nuclear factor kappa B activation was inhibited by DHA, hence, LPS‐induced proinflammatory cytokine synthesis of interleukin‐1β and tumor necrosis factor α was strongly attenuated. We suggest that DHA is highly anti‐inflammatory by targeting LPS receptor surface location, therefore reducing LPS action on microglia. This effect represents a new insight by which DHA modulates in the brain the expression of proinflammatory cytokines in response to bacterial product.
Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson’s disease aetiology
Authors: Caneda‐Ferrón Begoña , De Girolamo Luigi A. , Costa Teresa , Beck Katy E. , Layfield Robert , Billett E. Ellen
Published: March 2008

Mitochondrial impairment, glutathione depletion and oxidative stress have been implicated in the pathogenesis of Parkinson’s disease (PD), linked recently to proteasomal dysfunction. Our study analysed how these factors influence the various activities of the proteasome in human SH‐SY5Y neuroblastoma cells treated with the PD mimetics MPP+ (a complex 1 inhibitor) or dopamine. Treatment with these toxins led to dose‐ and time‐dependent reductions in ATP and glutathione and also chymotrypsin‐like and post‐acidic like activities; trypsin‐like activity was unaffected. Antioxidants blocked the effects of dopamine, but not MPP+, suggesting that oxidative stress was more important in the dopamine‐mediated effects. With MPP+, ATP depletion was a prerequisite for loss of proteasomal activity. Thus in a dopaminergic neuron with complex 1 dysfunction both oxidative stress and ATP depletion will contribute independently to loss of proteasomal function. We show for the first time that addition of MPP+ or dopamine to purified samples of the human 20S proteasome also reduced proteasomal activities; with dopamine being most damaging. As with toxin‐treated cells, chymotrypsin‐like activity was most sensitive and trypsin‐like activity the least sensitive. The observed differential sensitivity of the various proteasomal activities to PD mimetics is novel and its significance needs further study in human cells.
Influence of positive allosteric modulators on GABABreceptor coupling in rat brain: a scintillation proximity assay characterisation of G protein subtypes
Authors: Mannoury la Cour Clotilde , Herbelles Chloé , Pasteau Valérie , De Nanteuil Guillaume , Millan Mark J.
Published: March 2008

Little is known concerning coupling of cerebral GABABreceptors to G protein subtypes, and the influence of positive allosteric modulators (PAMs) has not been evaluated. These questions were addressed by an antibody‐capture/scintillation proximity assay strategy. GABA concentration‐dependently enhanced the magnitude of [35S]GTPγS binding to Gαo and, less markedly, Gαi1/3in cortex, whereas Gq and Gs/olf were unaffected. (R)‐baclofen and SKF97581 likewise activated Gαo and Gαi1/3, expressing their actions more potently than GABA. Similar findings were acquired in hippocampus and cerebellum, and the GABABantagonist, CGP55845A, abolished agonist‐induced activation of Gαo and Gαi1/3in all structures. The PAMs, GS39783, CGP7930 and CGP13501, inactive alone, enhanced efficacy and potency of agonist‐induced [35S]GTPγS binding to Gαo in all regions, actions abolished by CGP55845A. In contrast, they didnotmodify efficacies at Gαi1/3. Similarly, in human embryonic kidney cells expressing GABAB(1a+2)or GABAB(1b+2)receptors, allosteric modulators did not detectably enhance efficacy of GABA at Gαi1/3, though they increased its potency. To summarise, GABABreceptors coupled both to Gαo and to Gαi, but not Gq and Gs/olf, in rat brain. PAMs more markedly enhanced efficacy of coupling to Go versus Gi1/3. It will be of interest to confirm these observations employing complementary techniques and to evaluate their potential therapeutic significance.
MAPK and mTOR pathways are involved in cadmium‐induced neuronal apoptosis
Authors: Chen Long , Liu Lei , Luo Yan , Huang Shile
Published: March 2008

Cadmium (Cd) may be accumulated in human body through long‐term exposure to Cd‐polluted environment, resulting in neurodegeneration and other diseases. To study the mechanism of Cd‐induced neurodegeneration, PC12 and SH‐SY5Y cells were exposed to Cd. We observed that Cd‐induced apoptosis in the cells in a time‐ and concentration‐dependent manner. Cd rapidly activated the mitogen‐activated protein kinases (MAPK) including extracellular signal‐regulated kinase 1/2 (Erk1/2), c‐Jun N‐terminal kinase (JNK) and p38. Inhibition of Erk1/2 and JNK, but not p38, partially protected the cells from Cd‐induced apoptosis. Consistently, over‐expression of dominant negative c‐Jun or down‐regulation of Erk1/2, but not p38 MAPK, partially prevented Cd‐induced apoptosis. To our surprise, Cd also activated mammalian target of rapamycin (mTOR)‐mediated signaling pathways. Treatment with rapamycin, an mTOR inhibitor, blocked Cd‐induced phosphorylation of S6K1 and eukaryotic initiation factor 4E binding protein 1, and markedly inhibited Cd‐induced apoptosis. Down‐regulation of mTOR by RNA interference also in part, rescued cells from Cd‐induced death. These findings indicate that activation of the signaling network of MAPK and mTOR is associated with Cd‐induced neuronal apoptosis. Our results strongly suggest that inhibitors of MAPK and mTOR may have a potential for prevention of Cd‐induced neurodegeneration.
Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice
Authors: Lopez José R. , Lyckman Alvin , Oddo Salvatore , LaFerla Frank M. , Querfurth Henry W. , Shtifman Alexander
Published: March 2008

Neurodegeneration in Alzheimer’s disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg‐AD) mouse model of AD that exhibits intraneuronal accumulation of β‐amyloid proteins. Resting free Ca2+ concentration ([Ca2+]i), as measured with Ca2+‐selective microelectrodes, was greatly elevated in neurons from 3xTg‐AD and APPSWE mouse strains when compared with their respective non‐transgenic neurons, while there was no alteration in the resting membrane potential. In the absence of the extracellular Ca2+, the [Ca2+]i returned to near normal levels in 3xTg‐AD neurons, demonstrating that extracellular Ca2+contributed to elevated [Ca2+]i. Application of nifedipine, or a non‐L‐type channel blocker, SKF‐96365, partially reduced [Ca2+]i. Blocking the ryanodine receptors, with ryanodine or FLA‐365 had no effect, suggesting that these channels do not contribute to the elevated [Ca2+]i. Conversely, inhibition of inositol trisphosphate receptors with xestospongin C produced a partial reduction in [Ca2+]i. These results demonstrate that an elevation in resting [Ca2+]i, contributed by aberrant Ca2+entry and release pathways, should be considered a major component of the abnormal Ca2+ homeostasis associated with AD.
Brain‐derived neurotrophic factor over‐expression in the forebrain ameliorates Huntington’s disease phenotypes in mice
Authors: Gharami Kusumika , Xie Yuxiang , An Juan Ji , Tonegawa Susumu , Xu Baoji
Published: March 2008

Huntington’s disease (HD), a dominantly inherited neurodegenerative disorder characterized by relatively selective degeneration of striatal neurons, is caused by an expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels of brain‐derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF gene expression and anterograde transport of BDNF from cortex to striatum. However, roles of the BDNF reduction in HD pathogenesis have not been established conclusively. We reasoned that increasing striatal BDNF through over‐expression would slow progression of the disease if BDNF reduction plays a pivotal role in HD pathogenesis. We employed a Bdnf transgene driven by the promoter for the alpha subunit of Ca2+/calmodulin‐dependent kinase II to over‐express BDNF in the forebrain of R6/1 mice which express a fragment of mutant htt with a 116‐glutamine tract. The Bdnf transgene increased BDNF levels and TrkB signaling activity in the striatum, ameliorated motor dysfunction, and reversed brain weight loss in R6/1 mice. Furthermore, it normalized DARPP‐32 expression of the 32 kDa dopamine and cAMP‐regulated phosphoprotein, increased the number of enkephalin‐containing boutons, and reduced formation of neuronal intranuclear inclusions in the striatum of R6/1 mice. These results demonstrate crucial roles of reduced striatal BDNF in HD pathogenesis and suggest potential therapeutic values of BDNF to HD.
SYNCRIP, a component of dendritically localized mRNPs, binds to the translation regulator BC200 RNA
Authors: Duning Kerstin , Buck Friedrich , Barnekow Angelika , Kremerskothen Joachim
Published: March 2008

Dendritic transport of (m)RNA molecules and localized translation at post‐synaptic sites is connected to synaptic plasticity and memory formation. Brain cytoplasmic RNA, 200nt (BC200 RNA) is a brain‐specific, small non‐messenger RNA with a somatodendritic distribution in primate neurons. The transcript is a component of a ribonucleoprotein particle that is thought to act as a regulator of decentralized translation in dendrites. To elucidate the cellular function of the BC200 ribonucleoprotein particle, we purified BC200 RNA‐binding proteins from human brain. Here, we describe the interaction of human Synaptotagmin‐binding cytoplasmic RNA interacting protein (SYNCRIP) with BC200 RNA. SYNCRIP was recently characterized as a component of large mRNA transport granules in neurons and is probably involved in local protein synthesis at post‐synaptic sites. Our in vitro binding studies demonstrate that SYNCRIP interacts specifically with BC200 RNA and that binding is mediated through its N‐terminal RNA recognition motifs and the internal A‐rich region of BC200 RNA, respectively. Furthermore, immunoprecipitation experiments indicate an in vivo association of SYNCRIP and BC200 RNA in human brain. Thus, SYNCRIP may recruit BC200 RNA into mRNA transport complexes involved in the regulation of localized translation in dendrites.
Modulation of dopaminergic neurotransmission in rat striatum uponin vitroandin vivodiclofenac treatment1
Authors: Milusheva Elisaveta , Baranyi Mária , Kittel Agnes , Fekete Adam , Zelles Tibor , Vizi E. Sylvester , Sperlágh Beáta
Published: March 2008

Diclofenac (DCF) is a widely used non‐steroidal anti‐inflammatory drug, which also act as a mitochondrial toxin. As it is known that selective mitochondrial complex I inhibition combined with mild oxidative stress causes striatal dopaminergic dysfunction, we tested whether DCF also compromise dopaminergic function in the striatum. [3H]Dopamine ([3H]DA) release was measured from rat striatal slices afterin vitro(2 h, 10–25 μmol/L) orin vivo(3 mg/kg i.v. for 28 days) DCF treatment.In vitrotreatment significantly decreased [3H]DA uptake and dopamine (DA) content of the slices. H2O2(0.1 mmol/L)‐evoked DA release was enhanced. Intracellular reactive oxygen species production was not significantly changed in the presence of DCF. Afterin vivoDCF treatment no apparent decrease in striatal DA content was observed and the uptake of [3H]DA into slices was increased. The intensity of tyrosine hydroxylase immunoreactivity in the striatum was highly variable, and both decrease and increase were observed in individual rats. The H2O2‐evoked [3H]DA release was significantly decreased and the effluent contained a significant amount of [3H]octopamine, [3H]tyramine, and [3H]β‐phenylethylamine. The ATP content and adenylate energy charge were decreased. In conclusion, whereasin vitroDCF pre‐treatment resembles the effect of the mitochondrial toxin rotenone,in vivoit rather counteracts than aggravates dopaminergic dysfunction.
Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction
Authors: Nafia Imane , Re Diane B. , Masmejean Frédérique , Melon Christophe , Kachidian Philippe , Kerkerian‐Le Goff Lydia , Nieoullon André , Had‐Aissouni Laurence
Published: March 2008

Nigral depletion of the main brain antioxidant GSH is the earliest biochemical event involved in Parkinson’s disease pathogenesis. Its causes are completely unknown but increasing number of evidence suggests that glutamate transporters [excitatory amino acid transporters (EAATs)] are the main route by which GSH precursors may enter the cell. In this study, we report that dopamine (DA) neurons, which express the excitatory amino acid carrier 1, are preferentially affected by EAAT dysfunction when compared with non‐DA neurons. In rat embryonic mesencephalic cultures, l‐trans‐pyrrolidine‐2,4‐dicarboxylate, a substrate inhibitor of EAATs, is directly and preferentially toxic for DA neurons by decreasing the availability of GSH precursors and lowering their resistance threshold to glutamate excitotoxicity through NMDA‐receptors. In adult rat, acute intranigral injection of l‐trans‐pyrrolidine‐2,4‐dicarboxylate induces a large regionally selective and dose‐dependent loss of DA neurons and α‐synuclein aggregate formation. These data highlight for the first time the importance of excitatory amino acid carrier 1 function for the maintenance of antioxidant defense in DA neurons and suggest its dysfunction as a candidate mechanism for the selective death of DA neurons such as occurring in Parkinson’s disease.
Cell type‐specific subunit composition of G protein‐gated potassium channels in the cerebellum
Authors: Aguado Carolina , Colón José , Ciruela Francisco , Schlaudraff Falk , Cabañero Maria José , Perry Cydne , Watanabe Masahiko , Liss Birgit , Wickman Kevin , Luján Rafael
Published: March 2008

G protein‐gated inwardly rectifying potassium (GIRK/Kir3) channels regulate cellular excitability and neurotransmission. In this study, we used biochemical and morphological techniques to analyze the cellular and subcellular distributions of GIRK channel subunits, as well as their interactions, in the mouse cerebellum. We found that GIRK1, GIRK2, and GIRK3 subunits co‐precipitated with one another in the cerebellum and that GIRK subunit ablation was correlated with reduced expression levels of residual subunits. Using quantitative RT‐PCR and immunohistochemical approaches, we found that GIRK subunits exhibit overlapping but distinct expression patterns in various cerebellar neuron subtypes. GIRK1 and GIRK2 exhibited the most widespread and robust labeling in the cerebellum, with labeling particularly prominent in granule cells. A high degree of molecular diversity in the cerebellar GIRK channel repertoire is suggested by labeling seen in less abundant neuron populations, including Purkinje neurons (GIRK1/GIRK2/GIRK3), basket cells (GIRK1/GIRK3), Golgi cells (GIRK2/GIRK4), stellate cells (GIRK3), and unipolar brush cells (GIRK2/GIRK3). Double‐labeling immunofluorescence and electron microscopies showed that GIRK subunits were mainly found at post‐synaptic sites. Altogether, our data support the existence of rich GIRK molecular and cellular diversity, and provide a necessary framework for functional studies aimed at delineating the contribution of GIRK channels to synaptic inhibition in the cerebellum.