bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia
Authors: Lee Brendan , Dennis Julie A. , Healy Peter J. , Mull Benjamin , Pastore Lucio , Yu Hung , Aguilar-Cordova Estuardo , O’Brien William , Reeds Peter , Beaudet Arthur L.
Published: July 2002

The development of gene-replacement therapy for inborn errors of metabolism has been hindered by the limited number of suitable large-animal models of these diseases and by inadequate methods of assessing the efficacy of treatment. Such methods should provide sensitive detection of expressionin vivoand should be unaffected by concurrent pharmacologic and dietary regimens. We present the results of studies in a neonatal bovine model of citrullinemia, an inborn error of urea-cycle metabolism characterized by deficiency of argininosuccinate synthetase and consequent life-threatening hyperammonemia. Measurements of the flux of nitrogen from orally administered15NH4to [15N]urea were used to determine urea-cycle activityin vivo. In control animals, these isotopic measurements proved to be unaffected by pharmacologic treatments. Systemic administration of a first-generationE1-deleted adenoviral vector expressing human argininosuccinate synthetase resulted in transduction of hepatocytes and partial correction of the enzyme defect. The isotopic method showed significant restoration of urea synthesis. Moreover, the calves showed clinical improvement and normalization of plasma glutamine levels after treatment. The results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism in conjunction with a method for sensitively measuring correctionin vivo. These studies will be applicable to human trials of the treatment of this disorder and other related urea-cycle disorders.
Mutually exclusive expression of human red and green visual pigment-reporter transgenes occurs at high frequency in murine cone photoreceptors
Authors: Wang Yanshu , Smallwood Philip M. , Cowan Mitra , Blesh Diane , Lawler Ann , Nathans Jeremy
Published: July 2002

This study examines the mechanism of mutually exclusive expression of the human X-linked red and green visual pigment genes in their respective cone photoreceptors by asking whether this expression pattern can be produced in a mammal that normally carries only a single X-linked visual pigment gene. To address this question, we generated transgenic mice that carry a single copy of a minimal human X chromosome visual pigment gene array in which the red and green pigment gene transcription units were replaced, respectively, by alkaline phosphatase and β-galactosidase reporters. As determined by histochemical staining, the reporters are expressed exclusively in cone photoreceptor cells. In 20 transgenic mice carrying any one of three independent transgene insertion events, an average of 63% of expressing cones have alkaline phosphatase activity, 10% have β-galactosidase activity, and 27% have activity for both reporters. Thus, mutually exclusive expression of red and green pigment transgenes can be achieved in a large fraction of cones in a dichromat mammal, suggesting a facile evolutionary path for the development of trichromacy after visual pigment gene duplication. These observations are consistent with a model of visual pigment expression in which stochastic pairing occurs between a locus control region and either the red or the green pigment gene promotor.
In vivo
detection of amyloid plaques in a mouse model of Alzheimer's disease
Authors: Skovronsky Daniel M. , Zhang Bin , Kung Mei-Ping , Kung Hank F. , Trojanowski John Q. , Lee Virginia M.-Y.
Published: July 2002

Strategies for treating Alzheimer's disease (AD) include therapies designed to decrease senile plaque (SP) formation and/or promote clearance of SPs, but clinical trials of these treatments are limited by the lack of effective methods to monitor changes in plaque burden in the brains of living AD patients. However, because SPs are extracellular deposits of amyloid-β peptides (Aβ), it may be possible to eventually develop radioligands that cross the blood–brain barrier (BBB) and label SPs so they can be visualized by current imaging methods. As a first step toward the generation of such a radioligand, we developed a probe, [(
trans,trans
)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB)], and we report here that BSB has the following properties essential for a probe that can detect SPs
in vivo
. First, BSB sensitively labels SPs in AD brain sections. Second, BSB permeates living cells in culture and binds specifically to intracellular Aβ aggregates. Third, after intracerebral injection in living transgenic mouse models of AD amyloidosis, BSB labels SPs composed of human Aβ with high sensitivity and specificity. Fourth, BSB crosses the BBB and labels numerous AD-like SPs throughout the brain of the transgenic mice after i.v. injection. Thus, we conclude that BSB is an appropriate starting point for future efforts to generate an antemortem diagnostic for AD.
Cellular mechanisms for resolving phase ambiguity in the owl's inferior colliculus
Authors: Peña José Luis , Konishi Masakazu
Published: July 2002

Both mammals and birds use the interaural time difference (ITD) for
localization of sound in the horizontal plane. They may localize either
real or phantom sound sources, when the signal consists of a narrow
frequency band. This ambiguity does not occur with broadband signals. A
plot of impulse rates or amplitude of excitatory postsynaptic
potentials against ITDs (ITD curve) consists of peaks and troughs. In
the external nucleus (ICX) of the owl's inferior colliculus, ITD
curves show multiple peaks when the signal is narrow-band, such as
tones. Of these peaks, one occurs at ITDi, which is independent of
frequency, and others at ITDi ± T, where T is the tonal period.
The ITD curve of the same neuron shows a large peak (main peak) at ITDi
and no or small peaks (side peaks) at ITDi ± T, when the signal
is broadband. ITD curves for postsynaptic potentials indicate that ICX
neurons integrate the results of binaural cross-correlation in
different frequency bands. However, the difference between the main and
side peaks is small. ICX neurons further enhance this difference in the
process of converting membrane potentials to impulse rates. Inhibition
also appears to augment the difference between the main and side peaks.
Altered gating of opiate receptor-modulated K
+
channels on amygdala neurons of morphine-dependent rats
Authors: Chen Xueguang , Marrero Hector G. , Murphy Ricardo , Lin Yong-Jian , Freedman Jonathan E.
Published: July 2002

The molecular mechanism of tolerance to opiate drugs is poorly
understood. We have used single-channel patch–clamp recordings to
study opiate receptor effects on dissociated neurons from rat amygdala,
a limbic region implicated in addiction processes. A 130-pS inwardly
rectifying K
+
-preferring cation channel was activated by
μ opioid receptors in a membrane-delimited manner. After chronic
treatment of the rats with morphine, channel gating changed markedly,
with an approximately 100-fold decrease in open probability at a given
morphine concentration. The change in channel gating correlated both in
time course and in dose of morphine treatment with the development of
functional opiate dependence and appeared to arise at a step after
G-protein activation and before channel permeation by K
+
.
This decreased receptor–channel coupling appears to be large enough to
account quantitatively for opiate tolerance and may represent one of
the mechanisms through which tolerance occurs.
Abrupt climate change and thermohaline circulation: Mechanisms and predictability
Authors: Marotzke Jochem
Published: July 2002

The ocean's thermohaline circulation has long been
recognized as potentially unstable and has consequently been invoked as
a potential cause of abrupt climate change on all timescales of decades
and longer. However, fundamental aspects of thermohaline circulation
changes remain poorly understood.
An amino acid code for protein folding
Authors: Rumbley Jon , Hoang Linh , Mayne Leland , Englander S. Walter
Published: July 2002

Direct structural information obtained for many proteins supports
the following conclusions. The amino acid sequences of proteins can
stabilize not only the final native state but also a small set of
discrete partially folded native-like intermediates. Intermediates are
formed in steps that use as units the cooperative secondary structural
elements of the native protein. Earlier intermediates guide the
addition of subsequent units in a process of
sequential
stabilization
mediated by native-like tertiary interactions.
The resulting stepwise self-assembly process automatically constructs a
folding pathway, whether linear or branched. These conclusions are
drawn mainly from hydrogen exchange-based methods, which can depict the
structure of infinitesimally populated folding intermediates at
equilibrium and kinetic intermediates with subsecond lifetimes. Other
kinetic studies show that the polypeptide chain enters the folding
pathway after an initial free-energy-uphill conformational search. The
search culminates by finding a native-like topology that can support
forward (native-like) folding in a free-energy-downhill manner. This
condition automatically defines an initial transition state, the search
for which sets the maximum possible (two-state) folding rate. It also
extends the sequential stabilization strategy, which depends on a
native-like context, to the first step in the folding process. Thus the
native structure naturally generates its own folding pathway. The same
amino acid code that translates into the final equilibrium native
structure—by virtue of propensities, patterning, secondary structural
cueing, and tertiary context—also produces its kinetic
accessibility.
Emotion-induced changes in human medial prefrontal cortex: I. During cognitive task performance
Authors: Simpson Joseph R. , Snyder Abraham Z. , Gusnard Debra A. , Raichle Marcus E.
Published: July 2002

Regional cerebral blood flow (BF) was examined in regions of the medial prefrontal cortex (MPFC) with positron-emission tomography while subjects performed two cognitive tasks, reading nouns aloud and generating appropriate verbs for the same nouns. The control task was passive viewing of the same words. BF was reduced in regions of the MPFC during word reading and naïve verb generation, relative to a control state in which the subjects passively viewed nouns. Practicing verb generation produced improved performance, as measured by response time, which was strongly correlated with further reductions in MPFC and hypothalamic BF. After practice, when verb generation was performed on a novel list of words, reaction times slowed and the pattern of MPFC BF reverted to that seen in the word reading and naïve conditions. A separate behavioral study of the verb-generation task indicated that anxiety, high during naïve use-generation as measured by heart rate and self-report, decreased with practice on the task but returned with the introduction of a novel list of words. Taken together, these results suggest that the MPFC is part of a network, including the hypothalamus and brainstem, whose activity reflects a dynamic interplay between cognitive task performance and emotion.
Witchcraft, genealogy, Foucault
Authors: Russell Steven
Published: July 2002

This paper is a genealogical reflection on both the historiography of European witchcraft and the dynamics of witchcraft trials. I argue that traditional scholarly assumptions about the ‘unsophisticated’ nature of early modern European mentalities result in inadequate representations of accused witches and of the social contexts and processes of the trials. Genealogy, by contrast, problematizes fundamental notions such as reason, order, power and progress in ways that not only provide a different range of effective tools for the analysis of belief in witchcraft, but also underline its crucial significance for social theory. In the final section, an analysis of a typical trial is undertaken employing key genealogical insights into confession, torture, truth, governmentality, power, pleasure and pain.
Perceived discrimination and psychological adjustment among Russian‐speaking immigrant adolescents in Finland
Authors: Jasinskaja‐Lahti Inga , Liebkind Karmela
Published: July 2002

The aim of this study was to examine the relationship between perceived discrimination and psychological adjustment among immigrant adolescents. The subjects were 170 Russian‐speaking adolescents, all born in the former Soviet Union, aged between 12 and 19 years, who immigrated to Finland between 1987 and 1996. According to the results, self‐esteem served as a major mediator between perceived discrimination and psychological adjustment. The adolescents' experiences of parental support influenced their perceptions of discrimination and enhanced their self‐esteem, especially among the boys. Adherence to traditional values increased experiences of parental support, and also directly enhanced psychological adjustment. In addition, experiences of paternal support were found to be the most important for the boys, whereas experiences of maternal support were important for the girls.
Foreign Direct Investment and Development-agency Intervention: A Theoretical Model
Authors: Dewhurst J.H.L.
Published: July 2002

A model is proposed in which there are two regions that differ in terms of size. There are two firms, one located in each region, producing a homogeneous product. The firms have identical cost functions and act as Cournot oligopolists. Transporting the product between the two regions is costly. A foreign firm is to establish a plant in one of the regions. The foreign firm experiences higher fixed costs, but has lower marginal costs, than the domestic firms. The optimal location of the foreign firm's plant is determined. It is then assumed that there exists a regional-development agency (in the region not chosen by the foreign firm) that can commit funds to defray the fixed costs of the foreign firm, if it were to choose to locate in its region. The amount of the subsidy necessary to induce the foreign firm to alter its choice is determined and the implications for the levels and regional distributions of price, output, employment and welfare are compared with the position that would have arisen without the development agency's intervention.
Spatial Mismatch is not Always a Central-city Problem: An Analysis of Commuting Behaviour in Cleveland, Ohio, and its Suburbs
Authors: Gottlieb Paul D. , Lentnek Barry
Published: July 2002

One prediction of the spatial mismatch hypothesis is that black residents of the central city will have longer commutes than others. This prediction actually has two different components: African-Americans commute longer distances because they face discrimination in housing and/or labour markets; city-dwellers commute longer distances because entry-level jobs are scarce in the central city. This study uses a quasi-experimental design to distinguish between these two types of spatial mismatch. We compare 1990 commuting times for the residents of four Cleveland neighbourhoods: a poor black neighbourhood in Cleveland, a poor white neighbourhood in Cleveland, a lower-middle-class black suburb and a lower-middle-class white suburb. We were unable to find strong evidence that city residents suffered from poor job accessibility in 1990. We did find, however, that residents of the black suburb had longer commutes than residents of the white suburb—in spite of the fact that the black suburb was accessible to more skill-matched jobs. Probing further, we discovered that far more black than white suburbanites worked in the central city. This finding suggests that hiring discrimination or industry sector preferences on the part of black workers are potentially overlooked causes of racial differentials in commuting behaviour.
Trouble in E-topia: Knowledge as Intellectual Property
Authors: May Christopher
Published: July 2002

This article looks at the claims made about the city's new workplace, where information-related endeavour is leading to a new world of work. However, this can only be regarded as a positive step in labour relations if the central role of intellectual property in the information age is forgotten or obscured. After briefly laying out the claims made about the new age, the article identifies the continued importance for capitalists of controlling property rights, leading to an examination of the continuing property-based relations between information labour and capital(ists). Rather than representing an e-topia, the city's new mode of economic activity exhibits significant continuities with previous modes of capitalism. The claims for the empowerment of information and knowledge-workers in the new age are therefore optimistic at best and mistaken at worst.
Spatial Estimation of Housing Prices and Locational Rents
Authors: Chica Olmo Jorge
Published: July 2002

This work stems from the widely accepted hypothesis that housing price is determined by two types of characteristic: structural and locational. Under this hypothesis, a methodology is presented for the spatial estimation of housing prices and locational rents: the Iterative Residual Kriging (IRK) method. The methodological aspects are complemented by the presentation of an application of this methodology to the case of housing in Granada, Spain.
A Two-stage Econometric Analysis of the Housing Extension Decision in Kumasi, Ghana
Authors: Garrod Guy , Willis Ken , Graham Tipple A.
Published: July 2002

Much empirical work has been undertaken on housing production, investment levels and on the changes necessary to increase the supply of housing at a national level. The implicit assumption in these perspectives, that owners buy and sell housing as an adjustment process, is not realised in all housing markets around the world. In fact, in a number of developing countries houses are seldom bought or sold: one such country is Ghana. Here traditional economic perspectives on modelling an owner's decision to extend by comparing it with his decision to sell and move are largely irrelevant. This paper seeks to make a contribution to the analysis of housing supply by developing a housing extension model for the Asante culture in Ghana. The model is evaluated in a two-step econometric analysis of the decision to extend. In the first stage the probability of extending is modelled as a function of household characteristics, while the second stage predicts the amount spent on the extension.
Enterprising Behaviour and the Urban-Rural Shift
Authors: Keeble David , Tyler Peter
Published: July 2002

The paper presents and discusses new evidence on the nature and causes of the urban-rural shift of business activity and employment in England, derived from a matched pairs survey of over 1000 manufacturing and service businesses in remote rural, accessible rural and urban settlements. It reveals faster employment growth in rural firms, highlights the migration origins of and environmental influences on rural firm founders, and identifies significant urban-rural differences in the enterprising behaviour of companies. The implications of these findings for a new theoretical understanding of the reasons for the urban-rural shift are explored.
The Production Structure of Smaller Towns in Rural Regions in Latin America: A Case from Northern Costa Rica
Authors: Romein Arie
Published: July 2002

This paper deals with the production structures of small urban centres in peripheral rural regions in Latin America, a theme hardly investigated in a comprehensive and systematic way thus far. Examining the town of Ciudad Quesada, located in a specific type of region in northern Costa Rica, this paper is an attempt to narrow this gap in our knowledge on urban development. The analysis explores the relations between the internal segmentation of this town's production structure and some determining factors external to it. These external factors are the town's economic linkages with its regional hinterland, its functional integration within the national hierarchy of settlements, and elements of national development policy. The two different segments of the town's production structure appear to be based on this set of external factors in different ways.
Metropolitan and Non-metropolitan Employment Trends in the US: Recent Evidence and Implications
Authors: Gordon Peter , Richardson Harry W. , Yu Gang
Published: July 2002

Employment trends are analysed for the period 1969-94 across metropolitan and non-metropolitan areas (disaggregated spatially) by region and by sector. The decentralisation story is persistent but complex. The 1980s turns out to be an aberration (and even in that period, suburban growth was stronger than central-city growth), because since 1988 the vigorous non-metropolitan growth of the 1970s has resumed, and now has a clear rural emphasis.
Information Technology, Work Patterns and Intra-metropolitan Location: A Case Study
Authors: Giuliano Genevieve
Published: July 2002

Continued advances in information and communications technology are fundamentally changing the structure of the workplace and the organisation of work. Temporary work and self-employment are increasing, while job tenure is declining. This paper examines how these changes may affect both commuting patterns and metropolitan form. The growing number of workers who do not have a long-term attachment to a specific employer are termed 'contingent workers'. Using 1990 Public Use Micro Sample data for the Los Angeles region, the paper compares the commuting and location patterns of contingent and non-contingent workers. Results are quite mixed: residential location patterns do not differ significantly across worker categories, but commute length varies by category, with the self-employed having the shortest commutes.
Urban Planning amidst Ethnic Conflict: Jerusalem and Johannesburg
Authors: Bollens Scott A.
Published: July 2002

This article investigates the role and influence of urban planning in ameliorating or intensifying deep ethnic conflict. It is based on more than 75 interviews with urban planners and officials in Jerusalem and Johannesburg. Partisan Israeli planners utilise territorial policies that penetrate and diminish Palestinian land control. Post-apartheid urban policy in Johannesburg has pursued both conflict resolution and socioeconomic equity and is seeking to restructure apartheid geography. Both policy strategies are problematic. It is likely that partisan Israeli planning is creating an urban landscape of heightened political contestability and increased Jewish vulnerability. Johannesburg's equity planning is likely to be insufficient as economic forces shape new spatial inequalities. Urban planning must be reconceptualised in polarised cities so that it can contribute meaningfully to the advancement of ethnic peace.
The Price of Land for Housing in Trinidad: The Role of Regulatory Constraints and Implications for Affordability
Authors: Pamuk Ayse , Dowall David E.
Published: July 2002

Institutional and regulatory environments have a profound impact on land markets and prices. This paper argues that affordability of land and housing ownership in less developed countries is largely affected by cumbersome land transfer processes and an uncertain building permit approval process. It examines the impact of these constraints on land markets and affordability in Trinidad. By using Dowall's land market assessment methodology, the paper examines land price changes and land conversion patterns in the East-West Corridor region of Trinidad between 1989 and 1993. While prices of fully registered and serviced land have remained stable during this period (unlike many cases of 'skyrocketing' land prices reported in the literature), an examination of institutional and regulatory constraints suggests that land prices are likely to increase in the future when demand conditions become more favourable. These constraints have certainly played a significant role in the expansion of unauthorised housing settlements as documented by household survey results.
Analysing Mexican Population Concentration: A Model with Empirical Evidence
Authors: Dehghan Farhad , Vargas Uribe Guillermo
Published: July 2002

In this study, we analyse the economic determinants of population concentration in Mexico, estimating a time-series/cross-sectional model for 1895-1990 in which the Pareto coefficient is a measure of population concentration. The fundamental lesson of this paper is that there is a clear and unequivocal U-shaped pattern between population concentration and economic development. This finding was not confirmed in cross-national studies. Our results are consistent with central-place theory and suggest that as development proceeds, agglomeration benefits of large cities are exhausted and the optimum level of production is exceeded. Hence, government policies aimed at encouraging decentralisation may not interfere with economic growth and efficiency. Our findings point to the significant non-linear relationship between population concentration and a number of variables in the model including total population, urbanisation ratio, total land area, population density and central government expenditure. The significance of the central government expenditure coefficient in most versions of the model indicates that this variable plays an important role in shaping the city-size distribution in Mexico.
Levels of Immigrant Residential Concentration in Sydney and their Relationship with Disadvantage
Authors: Burnley Ian
Published: July 2002

Sydney on a world scale is a significant city of immigrants, having 1 020 000 overseas-born in 1991 and over 900 000 second-generation persons. The Australian 1991 Census included detailed questions on birthplace, language spoken in the home and English language competency. This allows us to measure the extent of immigrant segregation in Sydney on a more reliable basis than has hitherto been possible. With the exception of the populations born in the former Indochina, the Asian, Middle Eastern and Latin American groups were not more segregated than the more concentrated continental European groups. For almost all groups, the term segregation is inappropriate. Nevertheless, some of the ethnic concentrations are large and, in western Sydney and the inner southern suburbs, higher proportions of persons with limited English, lower incomes and no jobs reside in concentrations than elsewhere. Economic difficulties are being experienced, more so in several concentrations than among compatriots elsewhere. The concentrations, however, are not the cause of disadvantage and application of the term ghetto, or even enclave, to these concentrations is inappropriate and may contribute to the negative stereotyping of groups.
From Rejection to Resignation: Beneficiaries' Views on the South African Government's New Housing Subsidy System
Authors: Tomlinson Mary R.
Published: July 2002

South Africa's housing policy arose from a multi-party negotiating body, the National Housing Forum, made up of representatives of the housing sector and key political constituencies. Negotiations carried out over a two-year period (1992-94) resulted in a housing delivery approach whereby government facilitates a framework in which the private sector carries out the delivery of 'incremental housing'. This paper briefly describes the process through which the policy was formulated and presents the policy framework and the key programme through which the housing options are to be delivered. It offers the first attempt to gauge beneficiaries' feelings about their experience in accessing a subsidy; their views about their levels of satisfaction with their new housing option; and tests whether policy options negotiated by the stakeholders at the NHF matched the preferences of beneficiaries.
An Integrated Metropolitan Model Incorporating Demographic-economic, Land-use and Transport Models
Authors: Jun Myung-jin
Published: July 2002

This paper formulates an integrated metropolitan model which captures full intersectoral and interspatial relations as well as impacts on transport networks within a metropolitan area. To achieve this, the proposed model consists of three components: multizonal input-output linkages; land forecast models; and transport demand forecast models. Given the model structure, the proposed model can estimate economic impacts by type of secondary repercussions (indirect, and induced spillovers), by industry type and by zone. In addition, the proposed model will forecast the size of land by land-use type and by zone and estimate changes in traffic volumes on transport networks due to an urban policy. Moreover, the three components of the proposed model can be easily linked with GIS, presenting all the zone-specific information generated from the model on maps.
Constructing family climates: Chinese mothers’ reports of their co-parenting behaviour and preschoolers’ adaptation
Authors: McHale James P. , Rao Nirmala , Krasnow Aaron D.
Published: July 2002

This report examines how contemporary middle class urban mothers in Beijing, People’s Republic of China (PRC), characterise their own co-parenting conduct in the family. One hundred mothers of 4-year-old preschoolers (95% of whom were only-children) estimated how frequently they engaged in several different activities hypothesised to contribute to co-parenting solidarity. Mothers also reported on their children’s academic competence and behavioural adaptation. Self-reported coparenting activities factored into three major dimensions: behaviours promoting family integrity, co-parental conflict, and frequency of co-parental limit-setting or reprimand activities. Children whose mothers reported more frequent and active efforts to promote family integrity were rated as more academically competent than their peers. Children whose mothers acknowledged more frequent interparental discord and conflict were described both as showing more conduct problems, and as more anxious than their peers. Child conduct problems were also associated with mothers’ reports of more regular reprimand activities by the co-parenting partners. These co-parenting variables accounted for significant proportions of the variance in child behaviour measures over and above the contributions of maternal parenting practices. The implications of these findings for studies of co-parental conflict and solidarity within the PRC, and directions for future co-parenting research with Chinese families, are discussed.
The Relationship Between Cognitive Abilities and Social Abilities in Childhood: A Research on Flexibility in Thinking and Co-operation with Peers
Authors: Bonino Silvia , Cattelino Elena
Published: July 2002

This research is the first part of a project on the relationship between cognitive and social abilities in childhood, with special attention on the analysis of the relationship between ‘exibility in thinking and co-operative versus competitive solutions of social conflicts with peers. Flexibility is defined as the ability to suppress a response in order to ”nd a new one. The hypothesis is that the more ‘exible children are the more able they are to detach themselves from the conflict situation and more able to consider it in an integrated way—therefore they are more able to ”nd a co-operative solution. We studied a sample of 152 7-year-old children. In this research, the Wisconsin Card Sorting Task was used for the evaluation of ‘exibility in thinking. To evaluate co-operative and competitive behaviour, an interactive drawing task was used, where children were asked to draw together with tied pencils. Two children, of the same sex and of the same level (high or low) of ‘exibility, were put to work together in the interactive task. Results confirm the hypothesis, and indicate that the more ‘exible children are the more able they are to co-operate with their peers, to take turns, and to verbalise about other topics not related to the task
Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice
Authors: Sehata Shinya , Maejima Takanori , Watanabe Mayumi , Ogata Seiya , Makino Toshihiko , Tanaka Kohji , Manabe Sunao , Takaoka Masaya
Published: July 2002

The carcinogenic potential of chloroform was evaluated in a short-term carcinogenicity testing system using CB6F1 rasH2-Tg ( rasH2-Tg) mice. Chloroform was administered to rasH2-Tg males at doses of 28, 90, or 140 mg/kg and rasH2-Tg females at 24, 90, or 240 mg/kg by oral gavage for 26 weeks. Wild-type (non-Tg) male and female mice received doses of 140 mg/kg and 240 mg/kg, respectively. N-methyl- N-nitrosourea was administered to rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. In both the rasH2-Tg and non-Tg mice, there was no signifi cant increase in the incidence of neoplastic lesions by chloroform treatment. The incidence of hepatocellular foci in the rasH2- and non-Tg females receiving 240 mg/kg was increased. Forestomach tumors and malignant tumors occurred in most of the rasH2-mice in the positive control group. Swelling or vacuolation of hepatocytes, a toxic change induced by chloroform, occurred in both the rasH2-Tg and non-Tg mice. It is concluded that chloroform, a putative human noncarcinogen, did not show evidence of carcinogenic potential in the present study using rasH2-Tg mice. This study suggests that the rasH2-Tg mouse model may not be appropriate for detecting nongenotoxi c carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxi c carcinogens should be assessed with consideration of the results from the other ILSI-HESI project studies.
Neonatal Exposure to p-tert-octylphenol Causes Abnormal Expression of Estrogen Receptor α and Subsequent Alteration of Cell Proliferating Activity in the Developing Donryu Rat Uterus
Authors: Yoshida Midori , Takenaka Akiko , Katsuda Shin-Ichi , Kurokawa Yuji , Maekawa Akihiko
Published: July 2002

In the present study, we investigated immunohistochemicall y the time-course alterations in estrogen receptor α (ER) expression and cell proliferating activity in the developing uteri of Donryu rats exposed neonatally to a high dose p-tert-octylphenol (OP), an endocrine disrupting chemical (EDC). OP-treatment (sc injections of 100 mg/kg, every other day from postnatal days 1 to 15) induced an early and enhanced ER expression in the luminal epithelium compared with age-matched controls from postnatal day (PND) 10, and increased proliferating cell nuclear antigen (PCNA) positive cells up to PND21. At PND28, ER expression in the luminal epithelium of the OP-treated group was decreased, in association with decline in the luminal epithelial areas. PND14, the second week of life, is coincident with the normal time for differentiation when the luminal epithelium invaginates into the stroma to form uterine glands. OP-treatment, however, delayed and inhibited gland-formation, and suppressed ER expression in the invaginated-luminal and glandular epithelium at this time. These results indicate that ER expression in these sites is strongly linked with cell proliferating activity. In stromal cells, ER was expressed from PND6 in both groups without any PCNA positive cells, but significantly lower values were noted in the OP-treated group up to PND10. Our immunohistochemical investigation did not reveal any abnormalities in expression of the proto-oncogen e c-fos, mitotic inhibitor p21, or epidermal growth factor antigen, although the apoptotic index in the luminal epithelium was slightly increased in the OP-treated group. These results demonstrate neonatal effects of a high dose of OP, already detectable at PND10, with early and enhanced ER expression, resulting in increase of cell proliferative activity in the luminal epithelium, though expression in the glandular epithelium was suppressed in relation to inhibited gland-genesis. The present study thus suggests that neonatal exposure to high doses of EDCs with estrogenic activity can induce abnormal differentiation in the developing rat uteri via abnormal ER expression and subsequent alteration of cell proliferating activity.
The Role of a Toolkit in Mobilising Women in Local and Regional Development
Authors: Gilroy Rose , Booth Christine
Published: July 2002

This paper introduces UK readers to the EuroFEM Toolkit which has been developed with European Union (EU) funding. The Toolkit is a collection of methods and stories taken from women's projects in European member states and is aimed at supporting, encouraging and facilitating women's involvement in every sector of local and regional development. The context for the development of the Toolkit is set within the debate about gender mainstreaming and what this means for local and regional development.
Cross Talk between Adhesion Molecules: Control of N-cadherin Activity by Intracellular Signals Elicited by β1 and β3 Integrins in Migrating Neural Crest Cells
Authors: Monier-Gavelle Frédérique , Duband Jean-Loup
Published: July 2002

During embryonic development, cell migration and cell differentiation are associated with dynamic modulations both in time and space of the repertoire and function of adhesion receptors, but the nature of the mechanisms responsible for their coordinated occurrence remains to be elucidated. Thus, migrating neural crest cells adhere to fibronectin in an integrin-dependent manner while maintaining reduced N-cadherin–mediated intercellular contacts. In the present study we provide evidence that, in these cells, the control of N-cadherin may rely directly on the activity of integrins involved in the process of cell motion. Prevention of neural crest cell migration using RGD peptides or antibodies to fibronectin and to β1 and β3 integrins caused rapid N-cadherin–mediated cell clustering. Restoration of stable intercellular contacts resulted essentially from the recruitment of an intracellular pool of N-cadherin molecules that accumulated into adherens junctions in tight association with the cytoskeleton and not from the redistribution of a preexisting pool of surface N-cadherin molecules. In addition, agents that cause elevation of intracellular Ca2+ after entry across the plasma membrane were potent inhibitors of cell aggregation and reduced the N-cadherin– mediated junctions in the cells. Finally, elevated serine/ threonine phosphorylation of catenins associated with N-cadherin accompanied the restoration of intercellular contacts. These results indicate that, in migrating neural crest cells, β1 and β3 integrins are at the origin of a cascade of signaling events that involve transmembrane Ca2+ fluxes, followed by activation of phosphatases and kinases, and that ultimately control the surface distribution and activity of N-cadherin. Such a direct coupling between adhesion receptors by means of intracellular signals may be significant for the coordinated interplay between cell–cell and cell–substratum adhesion that occurs during embryonic development, in wound healing, and during tumor invasion and metastasis.
Antagonistic Roles of Neurofilament Subunits NF-H and NF-M Against NF-L in Shaping Dendritic Arborization in Spinal Motor Neurons
Authors: Kong Jiming , Tung Vivian W.-Y. , Aghajanian John , Xu Zuoshang
Published: July 2002

Dendrites play important roles in neuronal function. However, the cellular mechanism for the growth and maintenance of dendritic arborization is unclear. Neurofilaments (NFs), a major component of the neuronal cytoskeleton, are composed of three polypeptide subunits, NF-H, NF-M, and NF-L, and are abundant in large dendritic trees. By overexpressing each of the three NF subunits in transgenic mice, we altered subunit composition and found that increasing NF-H and/or NF-M inhibited dendritic arborization, whereas increasing NF-L alleviated this inhibition. Examination of cytoskeletal organization revealed that increasing NF-H and/or NF-M caused NF aggregation and dissociation of the NF network from the microtubule (MT) network. Increasing NF-H or NF-H together with NF-M further reduced NFs from dendrites. However, these changes were reversed by elevating the level of NF-L with either NF-H or NF-M. Thus, NF-L antagonizes NF-H and NF-M in organizing the NF network and maintaining a lower ratio of NF-H and NF-M to NF-L is critical for the growth of complex dendritic trees in motor neurons.
Direct Involvement of Ezrin/Radixin/Moesin (ERM)-binding Membrane Proteins in the Organization of Microvilli in Collaboration with Activated ERM Proteins
Authors: Yonemura Shigenobu , Tsukita Sachiko , Tsukita Shoichiro
Published: July 2002

Ezrin/radixin/moesin (ERM) proteins have been thought to play a central role in the organization of cortical actin-based cytoskeletons including microvillar formation through cross-linking actin filaments and integral membrane proteins such as CD43, CD44, and ICAM-2. To examine the functions of these ERM-binding membrane proteins (ERMBMPs) in cortical morphogenesis, we overexpressed ERMBMPs (the extracellular domain of E-cadherin fused with the transmembrane/cytoplasmic domain of CD43, CD44, or ICAM-2) in various cultured cells. In cultured fibroblasts such as L and CV-1 cells, their overexpression significantly induced microvillar elongation, recruiting ERM proteins and actin filaments. When the ERM-binding domains were truncated from these molecules, their ability to induce microvillar elongation became undetectable. In contrast, in cultured epithelial cells such as MTD-1A and A431 cells, the overexpression of ERMBMPs did not elongate microvilli. However, in the presence of EGF, overexpression of ERMBMPs induced remarkable microvillar elongation in A431 cells. These results indicated that ERMBMPs function as organizing centers for cortical morphogenesis by organizing microvilli in collaboration with activated ERM proteins. Furthermore, immunodetection with a phosphorylated ERM-specific antibody and site-directed mutagenesis suggested that ERM proteins phosphorylated at their COOH-terminal threonine residue represent activated ERM proteins.
Localized Depolymerization of the Major Sperm Protein Cytoskeleton Correlates with the Forward Movement of the Cell Body in the Amoeboid Movement of Nematode Sperm
Authors: Italiano Joseph E. , Stewart Murray , Roberts Thomas M.
Published: July 2002

The major sperm protein (MSP)-based amoeboid motility of Ascaris suum sperm requires coordinated lamellipodial protrusion and cell body retraction. In these cells, protrusion and retraction are tightly coupled to the assembly and disassembly of the cytoskeleton at opposite ends of the lamellipodium. Although polymerization along the leading edge appears to drive protrusion, the behavior of sperm tethered to the substrate showed that an additional force is required to pull the cell body forward. To examine the mechanism of cell body movement, we used pH to uncouple cytoskeletal polymerization and depolymerization. In sperm treated with pH 6.75 buffer, protrusion of the leading edge slowed dramatically while both cytoskeletal disassembly at the base of the lamellipodium and cell body retraction continued. At pH 6.35, the cytoskeleton pulled away from the leading edge and receded through the lamellipodium as its disassembly at the cell body continued. The cytoskeleton disassembled rapidly and completely in cells treated at pH 5.5, but reformed when the cells were washed with physiological buffer. Cytoskeletal reassembly occurred at the lamellipodial margin and caused membrane protrusion, but the cell body did not move until the cytoskeleton was rebuilt and depolymerization resumed. These results indicate that cell body retraction is mediated by tension in the cytoskeleton, correlated with MSP depolymerization at the base of the lamellipodium.
Bacterial Exposure Induces and Activates Matrilysin in Mucosal Epithelial Cells
Authors: López-Boado Yolanda S. , Wilson Carole L. , Hooper Lora V. , Gordon Jeffrey I. , Hultgren Scott J. , Parks William C.
Published: July 2002

Matrilysin, a matrix metalloproteinase, is expressed and secreted lumenally by intact mucosal and glandular epithelia throughout the body, suggesting that its regulation and function are shared among tissues. Because matrilysin is produced in Paneth cells of the murine small intestine, where it participates in innate host defense by activation of prodefensins, we speculated that its expression would be influenced by bacterial exposure. Indeed, acute infection (10–90 min) of human colon, bladder, and lung carcinoma cells, primary human tracheal epithelial cells, and human tracheal explants with type 1–piliated Escherichia coli mediated a marked (25–50-fold) and sustained (>24 h) induction of matrilysin production. In addition, bacterial infection resulted in activation of the zymogen form of the enzyme, which was selectively released at the apical surface. Induction of matrilysin was mediated by a soluble, non-LPS bacterial factor and correlated with the release of defensin-like bacteriocidal activity. Bacteria did not induce matrilysin in other cell types, and expression of other metalloproteinases by epithelial cells was not affected by bacteria. Matrilysin was not detected in germ-free mice, but the enzyme was induced after colonization with Bacteroides thetaiotaomicron. These findings indicate that bacterial exposure is a potent and physiologically relevant signal regulating matrilysin expression in epithelial cells.
Epidermal Growth Factor and Membrane Trafficking
Authors: Barbieri M. Alejandro , Roberts Richard L. , Gumusboga Aysel , Highfield Hilary , Alvarez-Dominguez Carmen , Wells Alan , Stahl Philip D.
Published: July 2002

Activated epidermal growth factor receptors recruit various intracellular proteins leading to signal generation and endocytic trafficking. Although activated receptors are rapidly internalized into the endocytic compartment and subsequently degraded in lysosomes, the linkage between signaling and endocytosis is not well understood. Here we show that EGF stimulation of NR6 cells induces a specific, rapid and transient activation of Rab5a. EGF also enhanced translocation of the Rab5 effector, early endosomal autoantigen 1 (EEA1), from cytosol to membrane. The activation of endocytosis, fluid phase and receptor mediated, by EGF was enhanced by Rab5a expression, but not by Rab5b, Rab5c, or Rab5a truncated at the NH2 and/or COOH terminus. Dominant negative Rab5a (Rab5:N34) blocked EGF-stimulated receptor-mediated and fluid-phase endocytosis. EGF activation of Rab5a function was dependent on tyrosine residues in the COOH-terminal domain of the EGF receptor (EGFR). Removal of the entire COOH terminus by truncation (c'973 and c'991) abrogated ligand-induced Rab5a activation of endocytosis. A “kinase-dead” EGFR failed to stimulate Rab5a function. However, another EGF receptor mutant (c'1000), with the kinase domain intact and a single autophosphorylation site effectively signaled Rab5 activation. These results indicate that EGFR and Rab5a are linked via a cascade that results in the activation of Rab5a and that appears essential for internalization. The results point to an interdependent relationship between receptor activation, signal generation and endocytosis.