bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukaemic stem cells
Authors: Blair A. , Pamphilon D. H.
Published: December 2003

Summary.  All haemopoietic cell lineages arise from multipotential self‐renewing stem cells that give rise to committed progenitor cells. These progenitor cells subsequently differentiate into more lineage‐committed cells with a restricted range of plasticity. A hierarchical order is considered to exist, where lineage commitment and differentiation are thought to be irreversible. As cells differentiate, they gradually lose the ability to self‐renew. The most primitive haemopoietic progenitor cells have the ability to reconstitute long‐term haemopoiesis in myeloablated recipients. However, as cells differentiate, there is an orchestrated silencing of some genes and activation of others, resulting in lineage commitment and generally a reduction in proliferative ability. Here, we discuss potential differences between normal and leukaemic stem cells, some of which may have therapeutic implications.
The cellular immunotherapy of viral infection
Authors: Moss P. A. H. , Cobbold M. , Craddock C.
Published: December 2003

Summary.  Viral infections remain a major problem for the patient who has undergone a stem cell transplant and the introduction of increasingly more intensive SCT regimens suggests that this will remain a significant concern for the immediate future. Advances in basic immunology have led to an improved understanding of how immune responses control individual viral infections and this information is now being directly applied to patient care with encouraging results. The application of cellular immunotherapy to the immunocompromised patient is one of the most exciting areas of clinical medicine and offers the prospect of significant clinical impact.
Quality issues in stem cell and immunotherapy laboratories
Authors: Smith L. , Lowdell M. W.
Published: December 2003

Summary.  The advent of the Code of Practice for Tissue Banks has led to the requirement for quality systems to be established in all laboratories involved in the production or processing of all cellular tissues to be used therapeutically. The quality system is all‐encompassing from process validations and quality assurance to the standard of facilities and staff training. This seems self‐evident to those working within the transfusion field but is a relatively novel concept to many hospital laboratories preparing transplant products such as bone marrow or peripheral blood derived haematopoietic stem cells. This review places the current guidelines in an historical context and explains many of the central tenets and requirements of the Code of Practice while outlining a process to facilitate preparation for accreditation.
1214 ± 5 Ma dyke from the Darling Range, southwestern Yilgarn Craton, Western Australia
Authors: Pidgeon R. T. , Cook T. J. F.
Published: December 2003

High thorium euhedral, twinned and elongate zircons from the felsic part of a mafic dyke located in the Archaean Yilgarn Craton approximately 30 km northeast of Perth and approximately 2 km east of the Darling Fault, have consistent 207Pb/206Pb ages of 1214 ± 5 Ma. This age is interpreted as the age of dyke emplacement and is identical, within the uncertainties, with other U–Pb dyke ages reported for the southwest Yilgarn Craton. The present result extends the known occurrence of ca 1210 Ma dykes to the western margin of the Yilgarn Craton and confirms earlier conclusions that a major mafic dyke emplacement occurred throughout the southern Yilgarn Craton during a short‐lived magmatic pulse at ca 1210 Ma.
Relationship Between Domestic Research and Development Activity and Technology Importation: An Empirical Investigation of Japanese Manufacturing Industries
Authors: Okabe Misa
Published: December 2003

This paper investigates the relationship between domestic research and development (R&D) activity and technological importation. We estimate the elasticity of factor inputs with respect to input prices using a cost minimization framework and time series data for Japanese manufacturing industries over the 1971–2000 period. The results show that domestic R&D activity and imported technology correlate with each other in the R&D‐intensive industries, and the relationship is affected by the characteristics of the industry. Moreover, it is found that domestic R&D activity tends to be correlated with capital saving, while imported technology tends to be correlated with increased capital formation and employment.
Persistence of Output Fluctuations Under Different Exchange Rate Regimes
Authors: Crosby Mark , Otto Glenn
Published: December 2003

In a recent paper, Giugale and Korobow (2000) present evidence that suggests that the time required by output to return to trend following a financial shock is faster under a flexible exchange rate regime than under a fixed exchange rate. In this paper, we use vector autoregression models to measure the persistence properties of output for a number of countries in the Asia–Pacific region. Our results suggest that output persistence is not uniquely related to a country's choice of exchange rate regime. The two countries in our sample with the least persistent output following a financial shock are Australia, where the exchange rate is fully flexible, and Hong Kong, where it is rigidly fixed via a currency board.
Similarities in the Consumption Patterns of the Five Asian Tigers
Authors: Selvanathan Eliyathahby Antony , Selvanathan Saroja
Published: December 2003

The five countries of Hong Kong, Japan, Korea, Singapore and Taiwan are considered to be the major Asian economic ‘Tigers’ behind Asia's growth in the late 1900s. In this paper, we analyze the consumption patterns of these five countries, using the most recent consumption data and employing the system‐wide approach. We find that the consumption data from these five countries support a number of empirical regularities, including the ‘law of demand’ and ‘Engel's law’. Based on the estimation results, we find that in all five countries, food, housing and medical care (except in Taiwan) are necessities, while clothing, durables (except in Singapore) and transport are luxuries. Demand for all the commodities is price inelastic. Furthermore, we find that the demand hypothesis, homogeneity, is acceptable for all five countries while Slutsky symmetry is acceptable only for Hong Kong, Singapore and Taiwan. We also find that the preference‐independence hypothesis is acceptable for all countries except Japan. Overall, consumption patterns of consumers appear to be similar across the five countries, while some differences exist between Japan and the other four countries.
Earnings Differentials Determinants Between Skills in the Malaysian Manufacturing Sector
Authors: Ismail Rahmah , Zin Ragayah Haji Mat
Published: December 2003

The Malaysian manufacturing sector has been experiencing a gradual change in its production process as it shifts from labor‐intensive to more capital‐intensive techniques. This has led to a change in the skills required by the industries where skilled workers are in greater demand and where the wage ratio between skills favors the skilled workers. There are many factors that can influence an indi‐vidual's earnings. These include educational attainment, job location, types of industries and sex. This paper attempts to measure the determinants of earnings differentials among skilled, semi‐skilled and unskilled workers in the Malaysian manufacturing sector. The analysis is based on a survey of 2065 workers in six major industries conducted in 1999. These are the electrical and electronics, textile, wood‐based, transport equipment, food and chemical industries. The determin‐ants of earnings differentials are obtained by using the coefficients of the earnings functions. These factors are decomposed into several categories, namely human capital, individual characteristics and the residual. The results reveal that human capital variables, which comprise education, training and experience, play a significant role in determining the earnings differentials, particularly between skilled and semi‐skilled workers and between semi‐skilled and unskilled workers.
Occupational Segregation and its Effect on Estimates of the Gender Wage Differential: Evidence from Brunei
Authors: Teo Siew Yean
Published: December 2003

This paper investigates the impact of the different occupational distributions of the gender groups on the gender wage differential in Brunei. We disaggregate occupational differences into explained and unexplained portions as this can provide better estimates of across‐occupation and within‐occupation wage differentials. Using data from the Brunei 1995 Labor Force Survey report, results indicated that the gender wage difference is approximately 60%. Unlike other studies, it is found that in Brunei the unexplained portion of occupational segregation has had an impact on gender wage differentials and accounts for approximately one‐third of the observed gap. Interestingly, the unexplained component of the within‐occupation gap is relatively less than in some developed economies. This is attributed to the effects of the large public sector in Brunei and its regulated pay scales.
Impact of International Trade with Asian Newly Industrialized Countries on Wages in the European Union
Authors: Cuyvers Ludo , Dumont Michel , Rayp Glenn
Published: December 2003

This paper deals with the effect of international trade with newly industrialized countries (NICs) on wage inequality in the European Union (EU). We apply a two‐stage mandated wage‐estimation procedure to assess the respective impact of trade and technology on the relative wages of low‐skilled workers. We find weak evidence of a positive impact on the wages of high‐skilled workers with regards to trade with high‐wage South‐East Asian NICs but no evidence for other groups of NICs. We also find evidence of technological change, induced by trade with high‐wage South‐East Asian NICs. However, this indirect effect of international trade seems to have reduced wage inequality in the EU.
Unemployment, Poverty and Income Disparity in Urban China
Authors: Xue Jinjun , Zhong Wei
Published: December 2003

This paper studies the issues of unemployment and poverty that have been appearing recently in urban China. It estimates the urban unemployment rate, poverty rate and income disparity using a new sample survey data set. Meanwhile, it analyzes the relationship between unemployment and poverty, and the effects of poverty on urban inequality. The main findings are that: (i) the urban unemployment rate reached 11.6% in 1999 and was a major cause of urban poverty; (ii) growing urban poverty is becoming the significant source of worsening urban inequality; and (iii) migrant households have an increasing influence on urban poverty and the pattern of urban income distribution. The paper concludes that urban income distribution has worsened since 1995, and urban unemployment and poverty are the major factors in this worsening.
Housing Prices, Mortgage Payments and Savings Behavior in Taiwan: A Time Series Analysis
Authors: Lin Chu‐Chia , Lai Yi‐Fang
Published: December 2003

After reaching its peak at the year of 1987, the saving rate of Taiwan dropped quickly in the late 1980s. At the same time, the real average housing prices in Taiwan had increased almost three times from 1987 to 1990. Why did the savings rate in Taiwan drop so quickly after 1987? Does it relate to the dramatic increase in housing prices? Although it has been confirmed that there is a negative wealth effect of housing price appreciation on savings, the estimated wealth effect on savings could be biased if the effect of mortgage payment (also known as forced savings) on saving is neglected. Applying quarterly data from 1981 to 2000 in Taiwan, we employ a time series analysis to compare two saving models, the traditional one and the one with forced saving. As we expected, the negative wealth effect of housing price appreciation on saving is smaller in the forced saving model than in the traditional saving model. By the estimated error correction models (ECMs), ignoring the impact of housing price appreciation on forced saving, the speed of short‐run adjustment in total saving would be significantly slower. For forecasting purposes, the forecast errors in ECM of the forced saving model are smaller than that in the total savings model.
Global schemas and local discourses in Cosmopolitan
Authors: Machin David , van Leeuwen Theo
Published: December 2003

This paper investigates the representation of female identity and practice in the U.K., Dutch, German, Spanish, Greek, Finnish, Indian and Taiwanese versions of Cosmopolitan magazine. It shows how a ‘problem–solution’ discourse schema underlies a range of articles that do not all use a problem–solution genre. While this schema is clearly global and occurs in all the versions of the magazine, it allows for local variation in terms of the kinds of problems and solutions it can accommodate. The schema is described as an interpretive framework which constructs social life as an individual struggle for survival in a world of risky and unstable relationships. The community of readers of the magazine is described as a globally dispersed and linguistically heterogeneous speech community which nevertheless shares an involvement with the same modalities and genres of language and the same linguistic constructions of reality and which can signify its allegiance to the values of the magazine through dress, grooming and other behaviours.
The globalisation of vernacular variation
Authors: Meyerhoff Miriam , Niedzielski Nancy
Published: December 2003

Work on variation and change in New Zealand English has identified a shift from older, more British‐like norms to newer, more American‐like ones in the last half century. The shift seems to affect lexical items, and phonological variables. This paper considers some general principles found, in the social sciences, to be associated with globalisation and considers what the theoretical and methodological implications are for the study of language variation if we talk about changes like those taking place in New Zealand English as being the effects of globalisation (or, more specifically, Americanisation). A study showing that New Zealanders have very different attitudes to variants that sociolinguists have lumped together in the past, suggests that globalisation with localisation is an important principle for variationists to take into account. It is suggested that variables hitherto analysed as being the consequence of globalisation might be better thought of as reflecting a ‘broadening of the vernacular base’.
English as a lingua franca: A threat to multilingualism?
Authors: House Juliane
Published: December 2003

In this paper I argue against the widespread assumption that the English language in its role as lingua franca is a serious threat to national languages and to multilingualism. I support this argument by making a distinction between ‘languages for communication’ and ‘languages for identification’. Further support for the stance against one‐sidedly attacking English as a killer language will be drawn from the findings of three research projects currently being carried out at Hamburg University, one on the impact English has on discourse norms in influential genres in other languages; the second one on the nature of interactions in English as a lingua franca; and the third one on so‐called ‘international degree programmes’, in which English is the language of instruction. Finally, I make some tentative suggestions for a new research paradigm for English as a lingua franca.
The politics of Europe 2002: flexibility and adjustment
Authors: Jones Erik
Published: December 2003

The European Union entered a new phase of integration in 2002. The single currency, the European Convention, and enlargement signalled progress. The conflict over the Stability and Growth Pact, the tensions between the member states, and the political turmoil in a number of core countries suggested retreat. This paper examines the resulting pattern of integration. It argues that the European Union is becoming more legalistic than leader‐oriented, and that it rests on common principles rather than accepting the imposition of some grand design. Such a European Union cannot challenge the United States for global leadership. But it is likely to prove stable nonetheless.
Enlargement and the European employment strategy: turbulent times ahead?
Authors: Ingham Mike , Ingham Hilary
Published: December 2003

The European Employment Strategy (EES) is set to remain centre stage as the EU embraces ten new member states. The evidence regarding the prospects of the accession countries meeting the increasingly explicit targets that the EES has set for the years up to 2010 does not yield a favourable prognosis.
Social dialogues—the state of the art a decade after Maastricht
Authors: Keller Berndt
Published: December 2003

The article asks whether social dialogues, according the procedures of the Social Protocol and the Amsterdam Treaty, have proved to be valuable instruments able to make major contributions to the development of social integration. More recent developments at the inter‐professional as well as at the sectoral level are evaluated. Furthermore, major trajectories for likely future trends at both levels are highlighted. The final part discusses the problem of whether social dialogues will profit from the introduction of new modes of governance, especially the more recently preferred open method of co‐ordination.
Multinationals and changing national business systems in Europe: towards the ‘shareholder value’ model?
Authors: Almond Phil , Edwards Tony , Clark Ian
Published: December 2003

This article reviews recent development in employment relations in MNCs, within the context of the varied and changing business systems within Western Europe. Focusing on Germany, France, Sweden and the UK, we analyse both the effects of national corporate governance systems on MNCs, and the extent to which MNCs specifically, and globalisation more widely, have affected the nature of national business and employment systems. While elements of a move towards a more ‘Anglo‐Saxon’, economically liberal model of corporate governance and employment relations can be detected in all four countries, this is far from complete. Cross‐national differences in business systems within Europe therefore continue to exert effects upon MNCs.
Ever larger unions: organisational restructuring and its impact on union confederations
Authors: Ebbinghaus Bernhard
Published: December 2003

Unions have responded to current membership decline and other organisational problems by restructuring via mergers, increasing union concentration within and across union confederations. A particular noted feature are amalgamations to form ‘super‐unions’. These conglomerate unions threaten to undermine the role played by confederations in respect of political voice, bargaining coordination, and service provision. Despite these mergers, union pluralism still prevails in many European countries with separate peak associations organised along employment/occupational status or political and religious lines. After comparing the recent merger waves and increased union concentration in western European countries, the consequences for union movements are discussed.
‘Fog in the Channel, continent isolated’: Britain as a model for EU social and economic policy?
Authors: Barnard Catherine , Deakin Simon , Hobbs Richard
Published: December 2003

A discourse on British ‘exceptionalism’ is currently developing according to which the UK's apparently ‘flexible’ economy should serve as a model for the rest of the EU. This is explored through two case studies concerning the transmission of regulatory practices from the continent to Britain (working time) and vice versa (takeover regulation). We suggest that a UK model of the firm constructed around shareholder value and untrammeled managerial prerogative is unlikely to have much resonance for other European systems, in which the term ‘flexibility’ has different connotations.
Gender equality still on the European agenda—but for how long?
Authors: Rubery Jill , Grimshaw Damian , Fagan Colette , Figueiredo Hugo , Smith Mark
Published: December 2003

While the momentum has certainly not yet disappeared from the gender equality agenda within Europe, the impact of that agenda remains patchy. Progress within individual member states has been significant but not always steady or cumulative. At the European level more attention has been paid to the gender pay gap but policy initiatives remain weak. The loss of the equal opportunities pillar in the new employment guidelines puts this momentum at risk but the new phase still includes commitments to an integrated strategy of gender mainstreaming and equal opportunities.
Bookshelf 2003
Authors: Greene Anne‐marie
Published: December 2003

Books reviewed:

Wolfgang Lecher, Bernhard Nagel and Hans‐Wolfgang Platzer. The Establishment of European Works Councils: From information committee to social actor.

Wolfgang Lecher, Hans‐Wolfgang Platzer, Stefan Rüb and Klaus‐Peter Weiner. European Works Councils: Developments, types and networking.

Wolfgang Lecher, Hans‐Wolfgang Platzer, Stefan Rüb and Klaus‐Peter Weiner. European Works Councils: Negotiated Europeanisation. Between statutory framework and social dynamic.

Gregor Murray, Jacques Bélanger, Anthony Giles and Paul‐André Lapointe (eds). Work and Employment Relations in the High‐Performance Workplace.

Bob Hancké. Large Firms and Institutional Change: Industrial Renewal and Economic Restructuring in France.

Daryl D’Art and Thomas Turner (eds). Irish Employment Relations in the New Economy.

Margaret Linehan, Michael J. Morley and James S. Walsh. International Human Resource Management and Expatriate Transfers: Irish Experiences.
Alteration of the fragile histidine triad gene early in carcinogenesis: an update
Authors: Ishii Hideshi , Ozawa Keiya , Furukawa Yusuke
Published: December 2003

An association between common chromosome fragile sites and frequent chromosomal deletions in cancer has been observed and led to the hypothesis that genes at fragile sites may play a role in tumor development. In 1996, the human fragile histidine triad gene, FHIT, was identified by positional cloning at 3p14.2, a chromosomal region spanning the carcinogen‐sensitive, common fragile site FRA3B. FHIT gene is lost and inactivated in a large fraction of tumors and early in carcinogenesis. A group of ancestral cancerous cells that carry FHIT alterations, expanding in succeeding cell generations, exhibits a hallmark in carcinogenesis scenario.
Clinical applications of DNA microarray analysis
Authors: Dudda‐Subramanya Raghunandan , Lucchese Guglielmo , Kanduc Darja , Sinha Animesh A.
Published: December 2003

Microarray technology provides a revolutionary macro‐genetic and bioinformatic‐rich platform for understanding human diseases. DNA microarrays facilitate the study of complex diseases, enabling several observations simultaneously that can become foundations for newer hypotheses—shifting us towards a non‐reductionist approach to biological phenomenon. This appears of particular value for scientific and clinical dissection of tumor pathologies. Despite the tremendous potential presented by microarray technology for the investigation of disease, concrete insights and advances that translate to the clinical setting are only recently beginning to be tapped. Here, we discuss specific examples of how microarray technology is being integrated into our ever‐evolving approach to clinical disease. We focus on molecular strategies for (a) disease classification, (b) disease outcome, and (c) disease mechanisms.
Regulation of cathepsin B and L expression in vitro in gastric cancer tissues by egg cystatin
Authors: Saleh Yousif , Siewiński Maciej , Kielan Wojciech , Ziółkowski Piotr , Gryboś Marian , Rybka Jacek
Published: December 2003

Background: Degradation of the basement membrane and surrounding extracellular matrix is likely to represent a key step in cancer invasion and metastasis. The purpose of this study was to determine whether gastric cancer tissues demonstrate higher cysteine proteases activities: cathepsins B and L during cancer progression in compression with non‐cancerous tissues. Methods: We measured the expression of both cathepsins B and L in 30 patients with gastric cancer tissues and non‐cancerous tissues activities by a fluorescence assay and immunohistochemical staining. We attempted to regulate cathepsin B and L expression using egg white cystatin. Results: The activities of cathepsins B and L were significantly higher in cancerous than in non‐cancerous tissues (P ≤ 0.0001). Activities of these enzymes decreased 18‐fold after treatment of tissue homogenates with 5 nM of purified egg white cystatin. Immunohistochemical staining was significant and positive expression of low molecular weight cystatin was observed on the tumor cell surface in gastric carcinoma. It was found that non‐cancerous tissues (control) were not stained with anti‐egg white antibody. Conclusion: Our experiment demonstrated that the cysteine peptidases cathepsins B and L may be useful for the early detection of gastric cancer. The results suggest that addition of egg white cystatin reduces the activities of cathepsins B and L to that of non‐cancerous values.
Vanadium suppresses sister‐chromatid exchange and DNA–protein crosslink formation and restores antioxidant status and hepatocellular architecture during 2‐acetylaminofluorene‐induced experimental rat hepatocarcinogenesis
Authors: Chakraborty Tridib , Ghosh Shilpi , Datta Subroto , Chakraborty Prabir , Chatterjee Malay
Published: December 2003

Vanadium is an important regulator of cellular growth, differentiation, and cell death, and thus has received increasing attention to be an effective cancer chemopreventive agent. In the present study, attempts have been made to investigate the in vivo antineoplastic effect of this micronutrient at the 0.5 ppm dosage in drinking water, by monitoring hepatic nodulogenesis and hepatocellular phenotype followed by antioxidant status and atomic absorption spectrometric estimation of some essential biometals during the multistage of carcinogenesis induced by 2‐acetylaminofluorene (2‐AAF; 0.05% in basal diet). Finally, sister‐chromatid exchange (SCE) and DNA–protein crosslink (DPC) formation, as potential biomarkers were estimated to find out the suppressive effect of vanadium at the molecular level. The results showed that vanadium administration throughout the experiment reduced the relative liver weight, nodular incidence (48.40%), total number, and multiplicity (63.91%), and altered the size of visible persistent nodules (PNs) with concurrent restoration of hepatic glutathione (P < 0.01), glutathione‐S‐transferase (P < 0.001) and manganese‐dependent superoxide dismutase (P < 0.001) activities as well as, hepatic zinc and copper contents (P < 0.001) when compared to the carcinogen control. Moreover, vanadium treatment significantly reduced SCE frequency (50.24%) and DPC coefficient (P < 0.001; 21.30%). Our results, thus, strongly suggest that supplementary vanadium at a dose of 0.5 ppm, when administered continuously throughout the study, than administered either in the initiation or promotion phase alone, is very much effective in suppressing neoplastic transformation during 2‐AAF‐induced in vivo rat hepatocarcinogenesis.
Inhibition of indoleamine 2,3‐dioxygenase suppresses NK cell activity and accelerates tumor growth
Authors: Kai Seiichiro , Goto Shigeru , Tahara Kouichirou , Sasaki Atsushi , Kawano Katsunori , Kitano Seigo
Published: December 2003

Indoleamine 2,3‐dioxygenase (IDO), a tryptophan catabolizing enzyme, is induced under various pathological conditions, including viral and bacterial infection, allograft rejection, cerebral ischemia, and tumor growth. We have previously reported that the expression of IDO mRNA was increased in some clinical cases of hepatocellular carcinoma in which the recurrence‐free survival rate in these IDO‐positive patients was significantly higher than that in patients without IDO mRNA induction in tumors. Additionally, IDO expressed in tumors was localized not to the tumor cells but instead to tumor‐infiltrating cells by immunohistochemistry. In this study, in order to elucidate the mechanisms underlying anti‐tumor effect of IDO, we investigated whether IDO inhibitor (1‐methyl‐dl‐tryptophan, 1MT) affects the growth of subcutaneous B16 tumors in mice. Subsequently, the activity of natural killer (NK) cells was investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA expression of B16 cells, B16 subcutaneous tumor, sprenocytes of mice, and human NK cells were studied by reverse transcription‐polymerase chain reaction. B16 subcutaneous tumor growth with or without IDO inhibition was observed and cytotoxic activity of NK cells were investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA was expressed in B16 subcutaneous tumor, splenocytes of tumor bearing mice, co‐cultured splenocytes with B16, and human NK cells. On day 14, after injection of B16 melanoma cells, the sizes of tumors in IDO‐inhibited mice were significantly larger than those in control mice. The cytotoxic activity of mice NK cells was reduced by IDO inhibition in vivo. In vitro inhibition of IDO, NK activity was reduced in dose‐dependent manner of 1MT. In conclusion, these results indicated that IDO plays an important role in anti‐tumor immunity by regulating cytotoxic activity of NK cells.
Progress in Methodology  Improved Reporter Gene Assays Used to Identify Ligands Acting on Orphan Seven‐Transmembrane Receptors
Authors: Kotarsky Knut , Nilsson Niclas E. , Olde Björn , Owman Christer
Published: December 2003

Abstract: Seven‐transmembrane G‐protein‐coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as “orphan” receptors. A pre‐requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence‐based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE® (high‐throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE® system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
Induction of NAD(P)H:quinone Reductase by Probucol: A Possible Mechanism for Protection against Chemical Carcinogenesis and Toxicity
Authors: Iqbal Mohammad , Okada Shigeru
Published: December 2003

Abstract: Dietary antioxidants protect laboratory animals against induction of tumours by a variety of chemical carcinogens. Among possible mechanism, protection against chemical carcinogenesis could be mediated via antioxidant–dependent induction of detoxifying enzymes, including quinone reductase and glutathione S‐transferase (GSH transferase). Probucol is used cholesterol‐lowering drug used in the clinic, with pronounced antioxidant effect that protect against chemical carcinogenesis and toxicity. In the present study we therefore examined the ability of probucol to induce activities of quinone reductase in the cytosolic fractions of various tissues of mice. Quinone reductase activity was increased significantly in 6 of 8 tissues examined from probucol‐fed mice. The greatest proportionate increase, to 1.8 times control levels, was observed in liver. Probucol also increased quinone reductase activities of forestomach, heart, kidney, lungs and spleen. Quinone reductase is a major enzyme of xenobiotic metabolism that carries out obligatory two‐electron reductions and thereby protects cells against toxicity of quinones. It is induced in many tissues coordinately with other enzymes that protect against electrophillic toxicity. The protective effects of probucol appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the non‐oxidative metabolism of a wide variety of xenobiotics. The induction of such enzyme, quinone reductase by probucol suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of probucol in various target organs.
6‐Ethyl‐N,N′‐bis(3‐hydroxyphenyl)[1,3,5]triazine‐2,4‐diamine (RS‐0466) Enhances the Protective Effect of Brain‐Derived Neurotrophic Factor on Amyloid β‐Induced Cytotoxicity in Cortical Neurones
Authors: Kubo Takekazu , Nishimura Satoko , Murasugi Takako , Kaneko Isao , Meguro Masaki , Marumoto Shinji , Kogen Hiroshi , Koyama Kazuo , Oda Tomiichiro , Nakagami Yasuhiro
Published: December 2003

Abstract: Amyloid β peptide in the senile plaques of patients with Alzheimer's disease is considered to be responsible for the pathology of Alzheimer's disease. We have previously reported that 6‐ethyl‐N,N′‐bis(3‐hydroxyphenyl)[1,3,5]triazine‐2,4‐diamine, RS‐0466, is capable of significantly inhibiting amyloid β‐induced cytotoxicity in HeLa cells. To determine various profiles of RS‐0466, we investigated whether RS‐0466 would enhance the neuroprotective effect of brain‐derived neurotrophic factor on amyloid β1–42‐induced cytotoxicity in rat cortical neurones. Consistent with previous observations, brain‐derived neurotrophic factor ameliorated amyloid β1–42‐induced cytotoxicity. Furthermore, co‐application of RS‐0466 enhanced the neuroprotective effect of brain‐derived neurotrophic factor. RS‐0466 also reversed amyloid β1–42‐induced decrease of brain‐derived neurotrophic factor‐triggered phosphorylated Akt. These results raise the possibility that RS‐0466 or one of its derivatives has potential to enhance the neuroprotective effect of brain‐derived neurotrophic factor, and could serve as a therapeutic agent for patients with Alzheimer's disease.
Mepivacaine Alters Vascular Responsiveness to Vasoconstrictors in Aortic Rings from Normal and Aortic‐Banded Rats
Authors: Mourouzis Constantinos , Pantos Constantinos , Mourouzis Iordanis , Saranteas Theodosios , Tesseromatis Christina , Kostopanagiotou Georgia , Karageorgiou Chariclia , Varonos Dennis , Cokkinos Dennis
Published: December 2003

Abstract: The present study investigated the effects of mepivacaine on the response of rat aorta to vasoconstrictors in normal and aortic‐banded animals. Cardiac hypertrophy was induced in Wistar rats by aortic banding, while sham‐operated animals served as controls. Isolated aortic rings with or without endothelium were contracted with potassium chloride and phenylephrine in the presence of mepivacaine (10−3 M). Maximal tension was measured at the highest concentration of potassium chloride and phenylephrine. Maximal response to potassium chloride was reduced in the presence of mepivacaine both in normal and aortic‐banded rings. As regards the vascular reactivity to phenylephrine, aortic rings with intact endothelium from aortic‐banded rats have shown increased response as compared to normal. After mepivacaine administration this difference between normal and aortic‐banded rats was abolished. In conclusion, in a model of cardiac hypertrophy such as that of aortic‐banding, increased response to α1‐adrenergic stimulation is observed, which is blunted by mepivacaine administration.
In Vitro Induction of Differentiation by Ginsenoside Rh2 in SMMC‐7721 Hepatocarcinoma Cell Line
Authors: Zeng Xiao‐li , Tu Zhi‐guang
Published: December 2003

Abstract: The aim of this study was to investigate the effects of ginsenoside Rh2 (G‐Rh2) on differentiation of SMMC‐7721 hepatocarcinoma cell line in culture. We studied G‐Rh2‐induced differentiation of SMMC‐7721 cells through cell proliferation, cell morphology, ultrastructure, cell cycle, cell function and metabolism. The proliferation of treated cells was inhibited, the morphology and ultrastructure seemed normal, the secretory amount and expression of α‐foetoprotein, and the specific activity of γ‐glutamyl transpeptidase, and heat‐resistant alkaline phosphatase were all significantly decreased, the secretory amount of albumin and alkaline phosphatase activity were remarkably increased, and the cell was arrested at the G1/G0 phase. Furthermore, G‐Rh2 induced elevated expression of the cyclin‐dependent kinase inhibitor p21WAF1 and p16INK4a, and declined expressions of cyclin D1 and cyclin E. In addition, G‐Rh2 almost completely inhibited telomerase activity, as measured by polymerase chain reaction‐based telomeric repeat amplification protocol coupled with enzyme‐linked immune sorbent assay, and human telomerase reverse transcriptase mRNA. Based on these data, it is suggested that G‐Rh2 could induce cell differentiation tending to normal and effectively reduce telomerase activity with affecting transcription levels of human telomerase reverse transcriptase, paralleling the induction of cell differentiation.
Inhibition by Uric Acid of Free Radicals that Damage Biological Molecules
Authors: Muraoka Sanae , Miura Toshiaki
Published: December 2003

Abstract: To clarify the antioxidative role of uric acid, its ability to scavenge carbon‐centered and peroxyl radicals and its inhibitory effect on lipid peroxidation induced by various model systems were examined. Uric acid efficiently scavenged carbon‐centered and peroxyl radicals derived from the hydrophilic free radical generator 2,2′‐azobis‐(2‐amidinopropane)‐dihydrochloride (AAPH). All damage to biological molecules, including protein, DNA and lipids induced by AAPH, was strongly prevented by uric acid. In contrast, α‐tocopherol had little effect on damage to biological molecules. Lipid peroxidation by the lipophilic free radical generator 2,2′‐azobis(2,4‐dimethylvaleronitrile) (AMVN) was little inhibited by uric acid, but not by α‐tocopherol. Copper‐induced lipid peroxidation was inhibited by uric acid and α‐tocopherol. NADPH‐ and ADP‐Fe3+‐dependent microsomal lipid peroxidation was efficiently inhibited by α‐tocopherol, but not by uric acid. Uric acid seems to scavenge free radicals in hydrophilic conditions to inhibit lipid peroxidation on the lipid‐aqueous boundary, and the antioxidation is only little in lipophilic conditions.
Melatonin Protects Against Mercury(II)‐Induced Oxidative Tissue Damage in Rats
Authors: Şener Göksel , Şehirli A. Özer , Ayanogˇlu‐Dülger Gül
Published: December 2003

Abstract: Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress‐like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N‐Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N‐acetylcysteine against Hg‐induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200–250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg‐melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin‐Hg‐melatonin group; 5) N‐acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg‐N‐acetylcysteine group, and 6) N‐acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N‐acetylcysteine‐Hg‐N‐acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end‐product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N‐acetylcysteine treatment. Since melatonin or N‐acetylcysteine administration reversed these responses, it seems likely that melatonin or N‐acetylcysteine can protect all these tissues against HgCl2‐induced oxidative damage.
Spontaneous Reversal of P‐Glycoprotein Expression in Multidrug Resistant Cell Lines*
Authors: Gréen Henrik , Lotfi Kourosh , Zackrisson Anna‐Lena , Peterson Curt
Published: December 2003

Abstract: Increased expression of P‐glycoprotein encoded by the mdr‐1 gene is a well‐characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P‐glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P‐glycoprotein expression in the presence (+) and absence (−) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30− and VCR150−) for 11 months. The P‐glycoprotein protein and mdr‐1 mRNA levels were determined at regular intervals using flow cytometry and real‐time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P‐glycoprotein and mdr‐1 mRNA during the whole period compared to wild type. As for the VCR30− and VCR150− subcultures, the expressions of P‐glycoprotein and mdr‐1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P‐glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P‐glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P‐glycoprotein and mdr‐1 mRNA levels as long as five months after drug withdrawal.
High-Probability Uniquantal Transmission at Excitatory Synapses in Barrel Cortex
Authors: Silver R. Angus , Lübke Joachim , Sakmann Bert , Feldmeyer Dirk
Published: December 2003

The number of vesicles released at excitatory synapses and the number of release sites per synaptic connection are key determinants of information processing in the cortex, yet they remain uncertain. Here we show that the number of functional release sites and the number of anatomically identified synaptic contacts are equal at connections between spiny stellate and pyramidal cells in rat barrel cortex. Moreover, our results indicate that the amount of transmitter released per synaptic contact is independent of release probability and the intrinsic release probability is high. These properties suggest that connections between layer 4and layer 2/3 are tuned for reliable transmission of spatially distributed, timing-based signals.
Managing Tragedies: Understanding Conflict over Common Pool Resources
Authors: Adams William M. , Brockington Dan , Dyson Jane , Vira Bhaskar
Published: December 2003

Conflicts over the management of common pool resources are not simply material. They also depend on the perceptions of the protagonists. Policy to improve management often assumes that problems are self-evident, but in fact careful and transparent consideration of the ways different stakeholders understand management problems is essential to effective dialogue.
A Muscleblind Knockout Model for Myotonic Dystrophy
Authors: Kanadia Rahul N. , Johnstone Karen A. , Mankodi Ami , Lungu Codrin , Thornton Charles A. , Esson Douglas , Timmers Adrian M. , Hauswirth William W. , Swanson Maurice S.
Published: December 2003

The neuromuscular disease myotonic dystrophy (DM) is caused by microsatellite repeat expansions at two different genomic loci. Mutant DM transcripts are retained in the nucleus together with the muscleblind (Mbnl) proteins, and these abnormal RNAs somehow interfere with pre-mRNA splicing regulation. Here, we show that disruption of the mouse
Mbnl1
gene leads to muscle, eye, and RNAsplicing abnormalities that are characteristic of DM disease. Our results support the hypothesis that manifestations of DM can result from sequestration of specific RNAbinding proteins by a repetitive element expansion in a mutant RNA.
Direct Observations of North Pacific Ventilation: Brine Rejection in the Okhotsk Sea
Authors: Shcherbina Andrey Y. , Talley Lynne D. , Rudnick Daniel L.
Published: December 2003

Brine rejection that accompanies ice formation in coastal polynyas is responsible for ventilating several globally important water masses in the Arctic and Antarctic. However, most previous studies of this process have been indirect, based on heat budget analyses or on warm-season water column inventories. Here, we present direct measurements of brine rejection and formation of North Pacific Intermediate Water in the Okhotsk Sea from moored winter observations. A steady, nearly linear salinity increase unambiguously caused by local ice formation was observed for more than a month.
Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios
Authors: Clark Andrew G. , Glanowski Stephen , Nielsen Rasmus , Thomas Paul D. , Kejariwal Anish , Todd Melissa A. , Tanenbaum David M. , Civello Daniel , Lu Fu , Murphy Brian , Ferriera Steve , Wang Gary , Zheng Xianqgun , White Thomas J. , Sninsky John J. , Adams Mark D. , Cargill Michele
Published: December 2003

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution. This evolutionary approach revealed an informative set of genes with significantly different patterns of substitution on the human lineage compared with the chimpanzee and mouse lineages. Partitions of genes into inferred biological classes identified accelerated evolution in several functional classes, including olfaction and nuclear transport. In addition to suggesting adaptive physiological differences between chimps and humans, human-accelerated genes are significantly more likely to underlie major known Mendelian disorders.