bluuebunny/crossref_metadata_2025 huggingface dataset:
Dilemmas and Developments: Eavan Boland Re-examined
Authors: Maguire Sarah
Published: July 2002

In ‘The Woman Poet: Her Dilemma’ (1986—7), the Irish poet Eavan Boland argued that women poets were obstructed on the one hand by traditional ideas of femininity and poetry, and on the other by the demands of separatist feminism. In ‘Dilemmas and Developments: Eavan Boland Re-examined’ Sarah Maguire argues that in recent years women poets have clearly achieved greater confidence as a result of changes in their audience. However, the underlying dilemma facing a woman poet — that of the tension between the demands of femininity and the role expected of a post-Romantic lyric poet — continues to remain unresolved.
Provisional Pleasures: The Challenge of Contemporary Experimental Women Poets
Authors: Tarlo Harriet
Published: July 2002

This article is an introduction to contemporary experimental poetry by women. It considers the reasons for the resistance to such work in this country. It refutes arguments made against it, for example that avant-garde writing is elitist or not related to women's experience. It further suggests why this writing, in particular in its complex engagement with issues of language, subjectivity and gender, should in fact be of great interest to the woman/feminist reader. In particular, it suggests parallels between the concerns of this work and those of feminist poststructuralism. Above all, throughout the piece, it attempts to introduce the ‘provisional pleasures’ of the contemporary avant-garde to the reader, introducing, quoting and providing multiple interpretations of the work of several diverse writers in this tradition. It aims to provide a sense of the linguistic and formal innovations of these writings, alongside a sense of their relevance to questions of female subjectivity and of women's relationship to the dominant discourses of our time.
‘Gone are the Days’: Bisexual Perspectives on Lesbian/Feminist Literary Theory
Authors: Naylor Ann Kaloski
Published: July 2002

In this article I offer a map of recent UK and US lesbian feminist literary theory which highlights the shifting and often paradoxical interpretations of lesbian sexuality as both real and as metaphorical. I focus on two key texts which offer overviews and analysis of the field from different sides of the Atlantic, which are both accessible, in the sense of being written from the perspective of ‘ordinary’ lesbians, rather than structuring lesbian feminist literary criticism around traditional critical concepts, and which also, unusually, offer some (small) comment on bisexuality. These two works are Bonnie Zimmerman's Safe Sea of Women (1992), and Palmer's Contemporary Lesbian Writing (1993). I argue that lesbian/feminist literary theory offers particular constructions of sexuality which, while challenging many of the assumptions of heterosexual feminist literary theory, largely ignores the bisexual content of much lesbian fiction, and consequently glosses over some of the tricky areas of gender and sexuality difference. Through this ‘les/bi’ reading I hope to encourage the figure of the bisexual woman to question both constructions and deconstructions of lesbian sexuality.
Children’s persistent lying, gender differences, and disruptive behaviours: A longitudinal perspective
Authors: Gervais Jean , Tremblay Richard E. , Desmarais-Gervais Lyse , Vitaro Frank
Published: July 2002

Background: Although lying by children can be a serious problem for parents and educators, there are hardly any longitudinal data to help understand its development. The aim of this study was to understand the stability of consistent lying from 6 to 8 years of age, and its association with other behaviour problems rated concurrently and subsequently. Methods: Teachers and mothers rated lying and disruptive behaviours of a population sample of boys ( N = 549) and girls ( N = 579) for three consecutive years when the children were 6, 7, and 8. Teachers also rated children’s disruptive behaviours at ages 10 and 11. Results: Mothers tended to rate their children as lying more often than teachers did. Girls were rated by both adults and across ages, as lying less than boys. The number of consistent liars (i.e., lying according to both adults at a given age) was the same at different ages. Persistent liars (consistent liars from ages 6 to 8) were rated more disruptive concurrently and subsequently by teachers. However, their disruptive behaviours did not increase from ages 6, 7, and 8 through ages 10 and 11 compared to other groups. Conclusions: Lying is common for 6- to 8-year-old children, but more frequent for males. Frequent lying, as reported by mothers and teachers, appears to become persistent by 7 years of age. Persistent lying was concurrently associated to disruptive behaviour problems. Some patterns of lying were also predictive of increases in disruptive behaviour but this finding was inconsistent and suggested the need for further research. Future studies need also to focus on the content of the lies, and their timing, to understand their function.
Mothers’ socialisation goals and evaluations of desirable and undesirable everyday situations in two diverse cultural groups
Authors: Leyendecker Birgit , Lamb Michael E. , Harwood Robin L. , Schölmerich Axel
Published: July 2002

Long-term socialisation goals and evaluations of infant behaviour in a variety of everyday contexts were studied among 45 mothers who had immigrated from Central America to the United States, and 41 mothers from European American backgrounds. In accord with expectations based on broad cultural constructs, mothers from Central America emphasised long-term socialisation goals related to Proper Demeanour. In addition, when describing and evaluating everyday situations, they were likely to attribute the desirability or undesirability of these situations to the child's own appropriate and cooperative behaviour, and were likely to highlight mutual enjoyment when describing preferred play situations. In contrast, Euro-American mothers emphasised long-term socialisation goals related to Self-Maximisation, and when describing undesirable everyday situations, stressed the role of external factors not under the child's control, presumably to preserve the child's self-esteem. However, it was also found that the Central American mothers endorse selected aspects of individualism related to promoting their children's economic and personal potential in the United States. These findings point not only to the multidimensional nature of individualism, but also to the heterogeneity of beliefs among Latino populations. The importance of studying within-group variation with regard to the individualism/sociocentrism construct is highlighted.
Adolescents’ judgements about the evidential basis for complex beliefs
Authors: Rowley M. , Robinson E.J.
Published: July 2002

Participants aged between 13 and 60 years read vignettes describing conflicting interpretations of limited evidence, explained why the different interpretations arose, and judged the importance of further evidence in resolving the dispute. Our focus was on participants’ views about how minds interpret information: Was their emphasis more on internal, psychological, or on external, information-based, factors in accounting for the existence of different interpretations? Participants of all ages agreed that further evidence would not be sufficient to resolve a value-laden dispute (whether youngsters should learn to drive) and explained the different views in terms of internal factors. However, younger participants discriminated less than older ones between the driving dispute and a dispute about a scientific/medical issue (the cause of a skin disease), and were less inclined to judge that views about the skin disease would be influenced by further evidence. We suggest that among people who accept the possibility of different interpretations of the same information, there are age-related differences in the importance placed on internal psychological processes in the construction of disparate views. Adolescents, compared with people who are older, seem to be particularly prone to assume that idiosyncratic interpretations will persist.
OfficeTech®: A New Paradigm in Office Services?
Authors: Winter Susan J. , Gill T. Grandon
Published: July 2002

officeTech® is a start-up company providing office assistance over the Internet. It certifies assistants’ skills, matches them with potential clients, supervises the quality of the work done and provides software tools for on-line collaboration. The founder, Gayle Barr, believed that this type of assistance would soon be the predominant model due to a convergence of several trends. First, advances in the Internet technology GroupWare and their acceptance by managers and professionals coupled with growth in the amount of coordination across time zones due to globalization and expansion of the number of telecommuting workers indicated that clients would be willing and able to work in a virtual relationship with their assistants. Second, extensive corporate downsizing and a large number of home-based new business start-ups had created a large pool of clients who did not have adequate permanent assistance available. In addition, many companies were now using large numbers of part-time and contract workers on an ongoing basis for clerical and professional positions. Thus, Barr reasoned, the technology was accessible, the need for part-time and temporary administrative assistance was apparent and clients were now sufficiently comfortable with such arrangements that the officeTech® concept should be feasible.
Practising Peer Review in Organizations: A Qualifier for Knowledge Dissemination and Legitimization
Authors: Bergquist Magnus , Ljungberg Jan , Lundh-Snis Ulrika
Published: July 2002

A key issue in many organizations is how to disseminate information in an effective way and, more importantly, how to make use of this information in order to create new knowledge. One way of addressing this problem is to focus on how information is socially transformed into knowledge. This includes how knowledge is handled in practice and how the knowledge produced is qualified as being something worth knowing and acting upon. Two well-established practices for doing this are the refereeing system and the peer review process. These are used in scientific communities as a means of validating and legitimating knowledge, for example by reviewing journal papers before publishing or project proposals before granting funds, etc. This paper argues that peer review is a useful concept when looking at knowledge creation and legitimization in organizations. The social meaning of peer review is to legitimize new knowledge by organizationally sanctioning it and thereby creating a platform for collective sense making. This paper uses an example from a field study in a pharmaceutical company in order to illustrate this argument. The study took place in a quality support department where the quality of health care products and processes was assessed. The organization had a need for fast and reliable updating of information that could influence how the production process of pharmaceuticals should be carried out. In order to cope with these problems the department established an ‘evaluation loop’, which shared several characteristics with the peer review process.
Many Rivers to Cross: From Ict to Knowledge Management Systems
Authors: Hendriks Paul H. J.
Published: July 2002

Several applications of information and communication technology (ICT) have gained considerable popularity as instruments for knowledge management. Some authors even seem to equate knowledge management with the introduction of specific ICT applications (intranets, groupware, etc.). However, the relationship between ICT and knowledge is no less problematic. Organizational knowledge and ICT refer to distinct sets of conceptions and establishing their relationship is far from trivial. The question then is how to assess the relationship between ICT and knowledge management. Several variables to be considered when answering this question have been identified in the literature: the enabling role of ICT for knowledge processes, the state of the ICT infrastructure, the level of knowledge required for using ICT, other user considerations, etc. However, a more encompassing perspective connecting these individual variables seems to be lacking. The aim of the present paper is to correct this. It argues that five dimensions determine the potential value of ICT applications for knowledge management. These dimensions are summarized in the following question. How and when will ICT, in interplay with other knowledge management measures (dimension 5), help knowledge (dimension 2) as a dynamic (dimension 4), institutional and action-related resource (dimension 3) realize its strategic potential (dimension 1)? The main argument in this paper is that, unless all five dimensions are addressed together, no satisfactory assessment of the status of an ICT application as a potential tool for knowledge management is feasible. Each of these dimensions is of a complex, multidimensional nature. The identification of the five dimensions is therefore only a first step. It needs a follow-up in the form of an elaboration of each dimension. This paper provides the groundwork for such an elaboration.
The Knowledge Management Tussle – Speech Communities and Rhetorical Strategies in the Development of Knowledge Management
Authors: Raub Steffen , Rüling Charles-Clemens
Published: July 2002

Knowledge management has become a major trend since the mid-1990s. Different professional communities, among them information systems/information technology (IS/IT) and more business management-oriented actors, have created strong conceptual ties with the idea of managing knowledge. This paper studies the structure and development of the knowledge management discourse over an 18-year period with an emphasis on the role of the IS/IT community in shaping this discourse. In order to do so, a content analysis of 434 article abstracts from the ABI/Inform database referring to ‘knowledge management’ was performed. The argument here is based on a theoretical framework derived from recent theorizing about popular management knowledge as fashion and it is assumed that different professional or ‘speech communities’ gathering around a concept such as knowledge management enter into competition for limited organizational resources. The paper's findings show the co-existence of two distinct speech communities involved in the knowledge management debate, focusing on either IS/IT or general management issues and they support the idea that both communities engage in a joint effort at sustaining knowledge management as a fashion field.
Sharing Knowledge across Boundaries
Authors: Ciborra Claudio U. , Andreu Rafael
Published: July 2002

Practical solutions concerning the strategic use of knowledge and its management depend upon the relevant organizational context. By applying the ‘learning ladder’ model (i.e. a compact way of describing the unfolding of multiple organizational knowledge creation, transformation and transfer processes), three different contexts are explored. First, the single firm is considered and the governance of its internal knowledge processes performed according to the tenets of the resource-based view of strategy. Second, the boundaries of the single firm are crossed and the characteristics of the processes of knowledge transfer and production between allied firms are considered. Finally, emerging features of how knowledge is managed among a large number of interdependent organizations and individuals are explored with reference to the case of open source software. The latter context highlights behaviours that seem, in a sense, at odds with the traditional principles of knowledge management. This is puzzling: conventional strategic and knowledge management frameworks break down precisely when dealing with the case of highly distributed, knowledge intensive businesses.
Globalization and Localization
Authors: Gibbs David
Published: July 2002

David Gibbs, Cox, K. R. (ed) 1997 SPACES OF GLOBALIZATION: REASSERTING THE POWER OF THE LOCAL New York: Guilford Press, £17.95 paper, ISBN 1 57230 199 6, pp. 292

Hines, C. 2000 LOCALIZATION: A GLOBAL MANIFESTO London: Earthscan, £10.99 paper, ISBN 1 85383 612 5, pp. 290
Job Creation by Assisted Rural Firms: a European North-South Perspective
Authors: Skuras Dimitris , Tzamarias Nick
Published: July 2002

The present paper reports results from a comparative analysis of the effectiveness of regional policy schemes in areas of Scotland and Greece. Discretionary schemes are of a lower gross cost per job than automatic ones in both countries. Additionality was found to be very high among all schemes in both countries. Results indicate that future policy design should be decentralised and highly adapted to local condition s. In the case of Greece, the dominant top-bottom style of policy making acts as major constraints in the adoption of more decentralised policy design and delivery mechanisms. In the case of Scotland such a task is easier to accomplish.
The socio‐political context of the development of Reading Recovery in New Zealand and England
Authors: Openshaw Roger , Soler Janet , Wearmouth Janice , Paige‐Smith Alice
Published: July 2002

This article uses the example of Reading Recovery (RR) to argue that those who engage in reading debates should focus not only on which reading programme appears to match desirable goals in children's literacy development but also strive for a more balanced appreciation of the complex socio‐political context of debates within which reading failure and its various remedies remain contestable. In turn this will lead to a more critical and more academically sophisticated scrutiny of literacy and its diverse purposes. The development of Reading Recovery in New Zealand and England illustrates how it is not simply the efficacy of individual programmes, but a combination of that efficacy and the political context at the micro‐ and macro‐levels that establishes, expands and eventually destabilizes new reading initiatives.
Economic Man in the Garden of Eden
Authors: Goodwin Craufurd D.
Published: July 2002

It has always been a puzzle why nineteenth century political economists were quite so gloomy. Why did they picture economic actors as motivated so single-mindedly by self-interest? Why did they see ahead the negative effects of diminishing returns, especially falling profit rates and rising rent shares, while all around them the evidence was pointing in the other direction? Why did they go on about the stationary state at a time when technical change was everywhere the norm? This gloom was hardly foreshadowed by the eighteenth century founders of political economy—Hume, Smith, and the Physiocrats (although for a contrary view see Robert Heilbroner 1973). It seems to have begun with Malthus and Ricardo, but it remained strong in the marginalist economists as well. Alfred Marshall and his followers rested their case for the necessity of careful marginal allocation of resources, and the intolerability of the costs imposed by trade unions and other rent seekers, on the ground that there were just not enough goods and services to go around. The notion of scarcity legitimized gloom.
How the Dismal Science Got its Name: Debating Racial Quackery
Authors: Levy David M.
Published: July 2002

Here is a fact that seems to surprise many deeply learned scholars. The term “dismal science” was applied to British political economy as the 1840s ended because of its role bringing about the emancipation of West Indian slaves in the 1830s. This paper addresses the consequences that follow from our ignorance of the role of classical economic theory in the anti-racial slavery coalition of Biblical literalists and utilitarians.
Economics' Past and Present: Historical Analysis and Current Practice
Authors: Hynes J. Allan
Published: July 2002

The place for the teaching of and research dealing with the history of economics continues to draw attention, at least from within our speciality. Recent examples are the History of Political Economy mini-symposium (1992) that was anchored to Margaret Schabas's paper and Donald Walker's affirming essay in theJournal of the History of Economic Thought(1999). The former asked whether the history of economics, given the neglect shown by mainstream economics, should be incorporated into history of science programs. The latter argued that this neglect is unfortunate because there is a place for the history of economics in the training of economists. (The neglect is documented by Aslanbegui and Naples (1997).) An important feature of Walker's essay is that the argument was based on structural aspects of the discipline. His point of departure was Donald Gordon's (1965) claim that there is little in the history of economic analysis that facilitates the understanding of current economics and the research problems with which it is concerned. Certainly the education of natural scientists, as Gordon noted, is consistent with this claim. George Stigler (1969) made a similar claim, and both more or less took the conclusion to be self-evident. Walker's response was that, at least among a variety of important sub-disciplines, there is not professional consensus and, therefore, there may not be a sharp distinction between current and past theory. This suggests that some form of historical analysis may be useful. Walker's paper moved the discussion away from arguments that begin with the presumption that every educated economist should be versed in the origins of economics. Instead, he focused on questions relating to history as a tool for understanding and for doing today's economics. In this respect, Walker returned to an issue addressed by Filippo Cesarano (1983)—they both focused on historical studies as a source of illumination for current economic analysis.
Equilibrium Proofmaking
Authors: Weintraub E. Roy , Gayer Ted
Published: July 2002

Each year, new economics Ph.D. students learn the proof of the existence of a competitive equilibrium as if it were a rite of passage. From the utility-maximizing behavior of consumers and the profit-maximizing behavior of firms, neophyte economists soon can demonstrate that under certain conditions there exists a competitive market-clearing general equilibrium price vector. While there are a number of proofs that establish the existence of such an equilibrium, the validity of these proofs is indubitable. Indeed, economists with even scant knowledge of the history of economics can identify Kenneth J. Arrow and Gerard Debreu's Econometrica paper as having provided the proof that settled the issue.
Psychiatric Care Management for Chronic Addictive Disorders: Conceptual Framework
Authors: Willenbring Mark L.
Published: July 2002

Coexisting mental and addictive disorders are common, and service systems are not well configured to treat them. Psychiatrists frequently feel lacking in skills to address both the addictive disorder and the mental illness. Although programs for treating “dual disordered” patients have been under development, specialized programs are likely to provide treatment for only a minority of patients. Furthermore, many patients either do not respond to them or simply refuse to participate. This article describes care management, a clinical approach that can be applied to coexisting disorders by any practitioner. Care management complements rehabilitation treatment and completes the continuum of care.
The Ums System for Exposure Assessment in Soil
Authors: Stubenrauch Steffen , Koschmieder Hans-Jürgen , Bauer Dirk , Doetsch Peter , Grünhoff Dirk , Hempfling Reinhold , Mahr Alexander
Published: July 2002

Risk assessment of contaminated sites intends to identify sources of dangers and, if possible, to quantify risks for objects of the public security that should be protected. The UMS system is an assistance device for the evaluation of human exposure to pollutants from hazardous waste sites. In addition to toxicological questions, the model considers the characteristics of pollution, site factors, and land use and tries to standardize the procedures and methods for the evaluation of a site-specific risk. With the UMS model, it is possible to describe the release and distribution of contaminants in soil and the intake, resorption, and effects in humans.
Concepts of the International Programme on Chemical Safety in the Assessment of Risks to Human Health from Exposure to Chemicals
Authors: Younes Maged , Sonich-Mullin Cynthia
Published: July 2002

The International Programme on Chemical Safety (IPCS) is a cooperative program of the World Health Organization, the International Labour Organization, and the United Nations Environment Programme. The main objectives of its risk assessment work are to provide, on a global basis, consensus assessments of priority chemicals (including pesticides) and to promote the development, validation, use, and harmonization of sound methodologies for risk assessment. The IPCS provides a number of comprehensive risk assessment documents, the most prominent of which are the Environmental Health Criteria monographs. In addition, evaluations of chemicals in food, air, and drinking water are conducted, and health-and environment-based guidelines for exposure are developed. In deriving guidance values for exposure to chemicals, the risk assessment paradigm of the National Academy of Sciences is followed. The development of guidance values for exposure is based on the calculation of a total intake from all sources. The process involves the identification of the critical effects and the pivotal studies, the derivation of a no (or lowest) observed adverse effect level, the application of (preferably data-derived) uncertainty factors, and the partitioning of the overall tolerable intake among all possible routes of exposure. Work on risk assessment methodologies is directed toward the promotion of scientifically sound approaches to evaluating risks to human health and the environment from exposure to chemicals. Special focus is placed on a project of harmonization of risk assessment methodologies.
Medical Device Risk Assessment Paradigm: Use and Case History
Authors: White R. D. , Cammack J. N. , Eyre R. J. , Wilson D. M.
Published: July 2002

In the medical device industry, risk assessment is required for product development and support, regulatory compliance, and manufacturing support. The risk assessment process can be divided into four major steps. The first step, hazard identification, involves determining whether exposure to an agent can cause an increased incidence of an adverse health condition (e.g., acute toxicity, cancer, birth defects, etc.). The next step in the risk assessment process is to characterize the dose-response relationship. Virtually all chemicals are toxic at some dose, and toxicity is dependent upon the circumstances of exposure, including the amount of substance available, the nature of contact with the substance, and the duration of contact. For both hazard identification and dose-response assessment, the use of scientifically valid data from any source, including data from published literature, is a central feature. Exposure assessment is the determination or estimation of the frequency and duration of human exposure to an agent. The last step in the risk assessment process is risk characterization. Risk characterization uses information from all three previous steps to estimate the probability of an adverse effect under the various conditions of described human exposure. All the components of risk assessment provide the framework for a working paradigm used in evaluating the safety of new or modified medical devices.
Alcohol, hypertension and the cardiovascular system: a critical appraisal
Authors: PUDDEY IAN B. , BEILIN LAWRENCE J. , RAKIC VALENTINA
Published: July 2002

Abstract Cross‐sectional and longitudinal population studies have provided a considerable corpus of evidence for an inverse association between light to moderate alcohol intake and both coronary artery disease and stroke. The formulation of balanced public health advice on the basis of such studies, however, needs to take into account the full spectrum of the effects of alcohol on the cardiovascular system, particularly its equally well documented effect to increase level of blood pressure and prevalence of hypertension. In this review, the broader implications of the association of alcohol with hypertension are discussed, principally in the context of the effect of higher levels of alcohol consumption to increase ischaemic and haemorrhagic stroke, left ventricular hypertrophy, congestive cardiomyopathy, cardiac arrhythmia and sudden cardiac death.
Assessment of Neurovascular Involvement by Malignant Musculoskeletal Tumors
Authors: Panicek David M. , Hilton Susan , Schwartz Lawrence H.
Published: July 2002

Determining the presence or absence of neurovascular involvement by a malignant musculoskeletal neoplasm is an
important aspect of local tumor staging. This article discusses issues concerning such assessments made by diagnostic
imaging techniques, including factors inherent to the patient and those related to imaging technology. The distinction
between tumor contact and tumor encasement is emphasized and illustrated.
Generalization of early metalinguistic skills in a phonological decoding study with first‐graders at risk for reading failure
Authors: Rivers Kenyatta O. , Lombardino Linda J.
Published: July 2002

This training study was designed to examine the effects of training letter‐sound correspondences and phonemic decoding (segmenting and blending skills) on the decoding skills of three first‐grade children identified to be at risk for reading failure. This training study was to examine the degree to which the subjects could readily learn decoding skills necessary for early reading and to determine the degree to which phonemic decoding training on CVC syllable structures generalize to untrained syllable structures. Three experimental subjects served as their own controls in a single‐subject multiple‐baseline design. Experimental subjects were compared to matched control subjects on their ability to decode real‐word and pseudo‐word stimuli and on formal test scores of reading and spelling. Following training, experimental subjects demonstrated substantial increases in their acquisition and generalization of phonological decoding skills, but revealed much smaller changes on pre‐test to post‐test measures of formal reading and spelling when compared to their matched control subjects.
Induction of the Angiogenic Phenotype by Hox D3
Authors: Boudreau Nancy , Andrews Catherine , Srebrow Anabella , Ravanpay Ali , Cheresh David A.
Published: July 2002

Angiogenesis is characterized by distinct phenotypic changes in vascular endothelial cells (EC). Evidence is provided that the Hox D3 homeobox gene mediates conversion of endothelium from the resting to the angiogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin αvβ3, and the urokinase plasminogen activator (uPA). Hox D3 antisense blocked the ability of bFGF to induce uPA and integrin αvβ3 expression, yet had no effect on EC cell proliferation or bFGF-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin αvβ3 and uPA. In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.
Lamin-binding Fragment of LAP2 Inhibits Increase in Nuclear Volume during the Cell Cycle and Progression into S Phase
Authors: Yang Li , Guan Tinglu , Gerace Larry
Published: July 2002

Lamina-associated polypeptide 2 (LAP2) is an integral membrane protein of the inner nuclear membrane that binds to both lamin B and chromatin and has a putative role in nuclear envelope (NE) organization. We found that microinjection of a recombinant polypeptide comprising the nucleoplasmic domain of rat LAP2 (residues 1–398) into metaphase HeLa cells does not affect the reassembly of transport-competent nuclei containing NEs and lamina, but strongly inhibits nuclear volume increase. This effect appears to be specifically due to lamin binding, because it also is caused by microinjection of the minimal lamin-binding region of LAP2 (residues 298–373) but not by the chromatin-binding domain (residues 1–88). Injection of the lamin-binding region of rat LAP2 into early G1 phase HeLa cells also strongly affects nuclear growth; it almost completely prevents the threefold nuclear volume increase that normally occurs during the ensuing 10 h. Moreover, injection of the fragment during early G1 phase strongly inhibits entry of cells into S phase, whereas injection during S phase has no apparent effect on ongoing DNA replication. Since the lamin-binding fragment of LAP2 most likely acts by inhibiting dynamics of the nuclear lamina, our results suggest that a normal function of LAP2 involves regulation of nuclear lamina growth. These data also suggest that lamina dynamics are required for growth of the NE and for nuclear volume increase during the cell cycle, and that progression into S phase is dependent on the acquisition of a certain nuclear volume.
Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages
Authors: Chen D. , Ji X. , Harris M.A. , Feng J.Q. , Karsenty G. , Celeste A.J. , Rosen V. , Mundy G.R. , Harris S.E.
Published: July 2002

Cumulative evidence indicates that osteoblasts and adipocytes share a common mesenchymal precursor and that bone morphogenetic proteins (BMPs) can induce both osteoblast and adipocyte differentiation of this precursor. In the present study, we investigated the roles of BMP receptors in differentiation along these separate lineages using a well-characterized clonal cell line, 2T3, derived from the mouse calvariae. BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions. To test the specific roles of the type IA and IB BMP receptor components, truncated and constitutively active type IA and IB BMP receptor cDNAs were stably expressed in these cells. Overexpression of truncated type IB BMP receptor (trBMPR-IB) in 2T3 cells completely blocked BMP-2–induced osteoblast differentiation and mineralized bone matrix formation. Expression of trBMPR-IB also blocked mRNA expression of the osteoblast specific transcription factor, Osf2/ Cbfa1, and the osteoblast differentiation-related genes, alkaline phosphatase (ALP) and osteocalcin (OC). BMP-2–induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB. Expression of a constitutively active BMPR-IB (caBMPR-IB) induced formation of mineralized bone matrix by 2T3 cells without addition of BMP-2. In contrast, overexpression of trBMPR-IA blocked adipocyte differentiation and expression of caBMPR-IA induced adipocyte formation in 2T3 cells. Expression of the adipocyte differentiation-related genes, adipsin and PPARγ, correlated with the distinct phenotypic changes found after overexpression of the appropriate mutant receptors. These results demonstrate that type IB and IA BMP receptors transmit different signals to bone-derived mesenchymal progenitors and play critical roles in both the specification and differentiation of osteoblasts and adipocytes.
Oncogenic Ras Downregulates Rac Activity, Which Leads to Increased Rho Activity and Epithelial–Mesenchymal Transition
Authors: Zondag Gerben C.M. , Evers Eva E. , ten Klooster Jean P. , Janssen Lennert , van der Kammen Rob A. , Collard John G.
Published: July 2002

Proteins of the Rho family regulate cytoskeletal rearrangements in response to receptor stimulation and are involved in the establishment and maintenance of epithelial cell morphology. We recently showed that Rac is able to downregulate Rho activity and that the reciprocal balance between Rac and Rho activity is a major determinant of cellular morphology and motility in NIH3T3 fibroblasts. Using biochemical pull-down assays, we analyzed the effect of transient and sustained oncogenic Ras signaling on the activation state of Rac and Rho in epithelial MDCK cells. In contrast to the activation of Rac by growth factor-induced Ras signaling, we found that sustained signaling by oncogenic RasV12 permanently downregulates Rac activity, which leads to upregulation of Rho activity and epithelial–mesenchymal transition. Oncogenic Ras decreases Rac activity through sustained Raf/MAP kinase signaling, which causes transcriptional downregulation of Tiam1, an activator of Rac in epithelial cells. Reconstitution of Rac activity by expression of Tiam1 or RacV12 leads to downregulation of Rho activity and restores an epithelial phenotype in mesenchymal RasV12- or RafCAAX-transformed cells. The present data reveal a novel mechanism by which oncogenic Ras is able to interfere with the balance between Rac and Rho activity to achieve morphological transformation of epithelial cells.
Expression and Function of αvβ3 and αvβ5 Integrins in the Developing Pancreas
Authors: Cirulli Vincenzo , Beattie Gillian M. , Klier George , Ellisman Mark , Ricordi Camillo , Quaranta Vito , Frasier Francine , Ishii Jennifer K. , Hayek Alberto , Salomon Daniel R.
Published: July 2002

Cell–cell and cell–matrix interactions play a critical role in tissue morphogenesis and in homeostasis of adult tissues. The integrin family of adhesion receptors regulates cellular interactions with the extracellular matrix, which provides three-dimensional information for tissue organization. It is currently thought that pancreatic islet cells develop from undifferentiated progenitors residing within the ductal epithelium of the fetal pancreas. This process involves cell budding from the duct, migration into the surrounding mesenchyme, differentiation, and clustering into the highly organized islet of Langerhans. Here we report that αvβ3 and αvβ5, two integrins known to coordinate epithelial cell adhesion and movement, are expressed in pancreatic ductal cells and clusters of undifferentiated cells emerging from the ductal epithelium. We show that expression and function of αvβ3 and αvβ5 integrins are developmentally regulated during pancreatic islet ontogeny, and mediate adhesion and migration of putative endocrine progenitor cells both in vitro and in vivo in a model of pancreatic islet development. Moreover, we demonstrate the expression of fibronectin and collagen IV in the basal membrane of pancreatic ducts and of cell clusters budding from the ductal epithelium. Conversely, expression of vitronectin marks a population of epithelial cells adjacent to, or emerging from, pancreatic ducts. Thus, these data provide the first evidence for the contribution of integrins αvβ3 and αvβ5 and their ligands to morphogenetic events in the human endocrine pancreas.
Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α
Authors: Novoa Isabel , Zeng Huiqing , Harding Heather P. , Ron David
Published: July 2002

Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on serine 51 integrates general translation repression with activation of stress-inducible genes such as ATF4, CHOP, and BiP in the unfolded protein response. We sought to identify new genes active in this phospho-eIF2α–dependent signaling pathway by screening a library of recombinant retroviruses for clones that inhibit the expression of a CHOP::GFP reporter. A retrovirus encoding the COOH terminus of growth arrest and DNA damage gene (GADD)34, also known as MYD116 (Fornace, A.J., D.W. Neibert, M.C. Hollander, J.D. Luethy, M. Papathanasiou, J. Fragoli, and N.J. Holbrook. 1989. Mol. Cell. Biol. 9:4196–4203; Lord K.A., B. Hoffman-Lieberman, and D.A. Lieberman. 1990. Nucleic Acid Res. 18:2823), was isolated and found to attenuate CHOP (also known as GADD153) activation by both protein malfolding in the endoplasmic reticulum, and amino acid deprivation. Despite normal activity of the cognate stress-inducible eIF2α kinases PERK (also known as PEK) and GCN2, phospho-eIF2α levels were markedly diminished in GADD34-overexpressing cells. GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2α in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2α and blocked attenuation of CHOP by GADD34. Expression of GADD34 is stress dependent, and was absent in PERK−/− and GCN2−/− cells. These findings implicate GADD34-mediated dephosphorylation of eIF2α in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.
Inhibition of β2Integrin–Mediated Leukocyte Cell Adhesion by Leucine–Leucine–Glycine Motif–Containing Peptides
Authors: Koivunen Erkki , Ranta Tanja-Maria , Annila Arto , Taube Seija , Uppala Asko , Jokinen Marjukka , van Willigen Gijsbert , Ihanus Eveliina , Gahmberg Carl G.
Published: July 2002

Many integrins mediate cell attachment to the extracellular matrix by recognizing short tripeptide sequences such as arginine–glycine–aspartic acid and leucine–aspartate–valine. Using phage display, we have now found that the leukocyte-specific β2 integrins bind sequences containing a leucine–leucine–glycine (LLG) tripeptide motif. An LLG motif is present on intercellular adhesion molecule (ICAM)-1, the major β2 integrin ligand, but also on several matrix proteins, including von Willebrand factor. We developed a novel β2 integrin antagonist peptide CPCFLLGCC (called LLG-C4), the structure of which was determined by nuclear magnetic resonance. The LLG-C4 peptide inhibited leukocyte adhesion to ICAM-1, and, interestingly, also to von Willebrand factor. When immobilized on plastic, the LLG-C4 sequence supported the β2 integrin–mediated leukocyte adhesion, but not β1 or β3 integrin–mediated cell adhesion. These results suggest that LLG sequences exposed on ICAM-1 and on von Willebrand factor at sites of vascular injury play a role in the binding of leukocytes, and LLG-C4 and peptidomimetics derived from it could provide a therapeutic approach to inflammatory reactions.
A conservedα-herpesvirus protein necessary for axonal localization of viral membrane proteins
Authors: Tomishima M.J. , Enquist L.W.
Published: July 2002

Pseudorabies virus, an α-herpesvirus, is capable of infecting the nervous system and spreading between synaptically connected neurons in diverse hosts. At least three viral membrane proteins (gE, gI, and Us9) are necessary for the spread of infection from presynaptic to postsynaptic neurons (anterograde spread) in infected rodents. To understand how these proteins effect anterograde spread between neurons, we analyzed the subcellular localization of viral proteins after infection of cultured rat sympathetic neurons with wild-type or mutant viruses. After Us9-null mutant infections but not gE-null mutant infections, only a subset of the viral structural proteins had entered axons. Surprisingly, capsid and tegument proteins but not viral membrane proteins were detected in axons. The spread of Us9 missense mutants in the rodent nervous system correlated with the amount of viral membrane proteins localized to axons. We conclude that the Us9 membrane protein controls axonal localization of diverse viral membrane proteins but not that of capsid or tegument proteins. The data support a model where virion subassemblies but not complete virions are transported in the axon. Our results provide new insight into the process of virion assembly and exit from neurons that leads to directional spread of herpesviruses in the nervous system.
Interactions of thrombospondins with α4β1 integrin and CD47 differentially modulate T cell behavior
Authors: Li Zhuqing , Calzada Maria J. , Sipes John M. , Cashel Jo Anne , Krutzsch Henry C. , Annis Douglas S. , Mosher Deane F. , Roberts David D.
Published: July 2002

Thrombospondin (TSP)-1 has been reported to modulate T cell behavior both positively and negatively. We found that these opposing responses arise from interactions of TSP1 with two different T cell receptors. The integrin α4β1 recognizes an LDVP sequence in the NH2-terminal domain of TSP1 and was required for stimulation of T cell adhesion, chemotaxis, and matrix metalloproteinase gene expression by TSP1. Recognition of TSP1 by T cells depended on the activation state of α4β1 integrin, and TSP1 inhibited interaction of activated α4β1 integrin on T cells with its counter receptor vascular cell adhesion molecule-1. The α4β1 integrin recognition site is conserved in TSP2. A recombinant piece of TSP2 containing this sequence replicated the α4β1 integrin–dependent activities of TSP1. The β1 integrin recognition sites in TSP1, however, were neither necessary nor sufficient for inhibition of T cell proliferation and T cell antigen receptor signaling by TSP1. A second TSP1 receptor, CD47, was not required for some stimulatory responses to TSP1 but played a significant role in its T cell antigen receptor antagonist and antiproliferative activities. Modulating the relative expression or function of these two TSP receptors could therefore alter the direction or magnitude of T cell responses to TSPs.
Murine Monocyte Chemoattractant Protein (MCP)-5: A Novel CC Chemokine That Is a Structural and Functional Homologue of Human MCP-1
Authors: Sarafi Mindy N. , Garcia-Zepeda Eduardo A. , MacLean James A. , Charo Israel F. , Luster Andrew D.
Published: July 2002

The chemokines are a large family of cytokines that control the recruitment of leukocytes in immune and inflammatory responses. We describe the isolation of a novel murine CC chemokine that, based on its biological and structural features, we have named monocyte chemoattractant protein (MCP)-5. MCP-5 mapped to the CC chemokine cluster on mouse chromosome 11 and was most closely related to human MCP-1 in structure (66% amino acid identity). Purified recombinant MCP-5 protein was a potent chemoattractant for peripheral blood monocytes, was only weakly active on eosinophils at high doses, and was inactive on neutrophils. MCP-5 induced a calcium flux in peripheral blood mononuclear cells, but not in purified murine eosinophils or neutrophils. Consistent with these results, MCP-5 induced a calcium flux in human embryonic kidney (HEK)-293 cells transfected with human and murine CCR2, a CC chemokine receptor expressed on monocytes. MCP-5 did not induce a calcium flux in HEK-293 cells transfected with CCR1, CCR3, or CCR5. Constitutive expression of MCP-5 mRNA was detected predominantly in lymph nodes, and its expression was markedly induced in macrophages activated in vitro and in vivo. Moreover, MCP-5 expression was upregulated in the lungs of mice following aerosolized antigen challenge of sensitized mice, and during the host response to infection with Nippostrongylus brasiliensis. These data indicate that MCP-5 is a novel and potent monocyte active chemokine that is involved in allergic inflammation and the host response to pathogens.