bluuebunny/crossref_metadata_2025 huggingface dataset:
Avoiding Boundaries: Antepenultimate Stress in a Rule-Based Framework
Authors: Beasley Tim , Crosswhite Katherine
Published: August 2003

This article is part of a larger study investigating antepenultimate stress and final nonparsing (extrametricality). Here we examine the rule-based implementation of final nonparsing in Idsardi 1992. We present an in-depth analysis for Macedonian, a language well known for ante-penultimate stress. We argue that nonparsing does not account for all the data, and we propose enriching the inventory of avoidance constraints to directly derive peripheral ternarity. This analysis allows us to account for several details that are not addressed by previous analyses (Idsardi 1992, Halle and Kenstowicz 1991). We also consider crosslinguistic ramifications and suggest that some cases of ternarity result from generalized boundary avoidance.
Rethinking Complementizer Agreement: Agree with a Case-Checked Goal
Authors: Carstens Vicki
Published: August 2003

Agree(X, Subj) accounts for all agreement in West Germanic: complementizer agreement (CA) results from an Agree relation between uninterpretable φ-features of Fin0 (Rizzi 1997) and φ-features of the subject; subject-verb agreement (SA) spells out uninterpretable φ-features of T0 on V0 raised to T0, even in OV clauses (Haegeman 2000). Although DPs need Case to participate in Agree relations (Chomsky 2000), deletion-marked Case remains syntactically accessible until the next strong phase (Pesetsky and Torrego 2001), allowing CA and SA to cooccur. In Frisian, ‘that’ cannot agree in embedded VO clauses because it is in Force; the verb is in Fin0, bearing CA (contra Zwart 1997).
The Distribution of a Subject Clitic Pronoun in a Franco-Provençal Dialect and the Licensing of Pro
Authors: Crousaz Isabelle De , Shlonsky Ur
Published: August 2003

We study the distribution of null subjects in one Franco-Provençal variety. These are possible in root declaratives, obligatory in embedded subject position, and impossible in root wh-questions as well as in the company of weather predicates. We approach null subjects indirectly, by investigating the distribution of one subject clitic, arguing that its optionality in some contexts is due to the possibility of moving pro to a peripheral topic position, where formal licensing is not required. We also discuss the circumstances in which an overt complementizer and a robustly inflected verb license pro, rendering the clitic redundant. The comparative interest of this dialect is that it reveals synchronically the three mechanisms of pro licensing available in Romance diachronically. These are (a) association with rich verbal inflection, (b) government by a complementizer, and (c) doubling by a clitic. We contend that the syntax is sensitive to the formal relationship between an XP and a head that these three mechanisms instantiate.
Movement Out of Control
Authors: Landau Idan
Published: August 2003

This article is a comprehensive critique of the reductionist view of control advocated in recent minimalist studies, most notably Hornstein 1999. The core of this view is the claim that obligatory control should be collapsed with raising, and nonobligatory control with pronominal coreference. I argue that Hornstein's theory (a) overgenerates nonexisting structures and interpretations, (b) fails to derive a wide range of well-known raising/control contrasts, and (c) involves unstated stipulations belying the appeal to Occam's razor.
Building Policy from Practice: District Central Office Administrators' Roles and Capacity for Implementing Collaborative Education Policy
Authors: Honig Meredith I.
Published: August 2003

This article defines district central office administrators' roles and capacity to support the implementation of school-community partnerships. Findings come from a strategic case study of central office administrators in Oakland, California (1990-2000). Using concepts from organizational learning theory for the theoretical framework, this study demonstrates that supporting collaboration departs significantly from central office administration-as-usual and highlights conditions and capital that enable central office administrators' new roles.
Spatial Patterns and Processes in a Longitudinal Framework
Authors: Waldorf Brigitte
Published: August 2003

This article explores the conceptual equivalence between hazard models applied to both temporal data and distance data by focusing on the `at-risk' concept, which is central to longitudinal models but has not received sufficient attention in the application of hazard models in spatial settings. A proper conceptualization in a spatial (distance) setting is based on distant-dependent Markovian transition probabilities describing the risk of switching between states. Such a conceptualization is possible for continuous spatial processes, as well as for point-generating processes leading to spatial point patterns. Hazard models for a series of scenarios simulating various point generation trajectories are compared. This process-oriented perspective is further augmented by explicitly accounting for temporal dimensions (speed) of point-generating processes.
Differential Regional Effects of Monetary Policy: A Geographical SVAR Approach
Authors: Di Giacinto Valter
Published: August 2003

The study of possible asymmetric effects of monetary policy at a spatially disaggregated scale has received increasing attention in the literature. Different econometric approaches have been proposed to quantify the differences in monetary policy transmission, such as large-scale simultaneous equations models or structural vector autoregressive (SVAR) models. This article builds on the SVAR approach and extends it by incorporating geographical information, using spatial econometric techniques. The author employs information on spatial proximity to derive parameter constraints, enabling joint estimation for medium- and large-sized panels. Moreover, the use of spatial a priori information makes it possible to identify and estimate contemporaneous spatial spillover effects. Specific attention is paid to parameter identification when introducing the model. Subsequently, the author discusses parameter estimation, which is complicated by the simultaneous spatial dependence structure and the need to impose complex parameter constraints. An empirical application is provided with respect to U.S. states.
Spatial Econometric Modeling of Regional Convergence in Continuous Time
Authors: Arbia Giuseppe , Paelinck Jean H. P.
Published: August 2003

In this article, the authors use a continuous-time framework to model the potential convergence dynamics in a group of regions. They propose a model based on the classical Lotka-Volterra predator-prey system of two equations—a model originally proposed by Samuelson in 1971 to perform dynamic economic analysis—and extend the model to the case of more than two regions by introducing dependence on neighboring regions. The authors state the conditions under which the system of regions moves toward a mathematically stable point of convergence and show that the model can be seen as more general than the popular β -convergence model. Finally, they also consider statistical inference and introduce a discrete approximate solution based on simultaneous dynamic least squares to estimate the parameters of the model.
The New Politics, History and History of Religions: The World After 11 September 2001
Authors: Antes Peter
Published: August 2003

Many people say that the world changed after 9/11 and that nothing is as it was. What does indeed appear true is that international politics has to change and come up with a new concept with new tasks and principles appropriate to the requirements of the situation.

This brief contribution aims to suggest an outline by tackling the transformation of the old concept of politics into a new politics, a politics adapted to the challenge thrown down by the events of 11 September 2001 that so shocked the world. A first draft of the tasks required will define the new principles on which these tasks are based, and will conclude with a short observation on the future political analysis of the university disciplines involved.
Religious Pluralism and Crises of Identity
Authors: Filoramo Giovanni
Published: August 2003

At the dawn of the new millennium religion is going through some radical changes: the first of these is related to the fact that the processes of secularization have had an influence on traditional religions, are doing so today and will continue to do so, starting with Christianity in its different forms, but they have not precipitated the decline of religion as an institutional and public factor and still less the decline of faith as a private phenomenon.

What we are experiencing is rather a huge process of transformation and adaptation of the religious as a private dimension and religion as an institutional factor, resulting in a profound metamorphosis of the socio-cultural situation (see Lyon, 2000). The two main elements of the change are as follows: the triumph of the mass media and consumer society and the processes of globalization (Kurz, 1995) are radically changing the very face of religion: groups and movements with a clear religious identity are involved in a relentless process that is at the same time a process of adaptation and resistance to these changes. The outcome of this process is uncertain, but there is no doubt that it is only where religions prove they are capable of using and adapting their messages of salvation to the new mass media system that they will be able to survive and maybe even spread.
Muslim Women: Between Cliché and Reality
Authors: Ali Wijdan
Published: August 2003

Clichés about the Orient and Oriental women, which imposed themselves with considerable force on the popular imagination, have been perpetuated in Europe since the Middle Ages. The projection of evil onto marginal or ineffectual groups within a society has always been an easy and useful method for making scapegoats. Jews in Medieval Europe were stereotyped and tried for a number of fictitious crimes such as poisoning wells, killing children for their blood and crucifying and cannibalizing their victims. Along the same lines women were associated with the devil and regarded as enemies of the Church, hence the witch-hunts that tried women for sexual voraciousness, cannibalism and consorting with evil spirits. The projection of evil onto an alien culture was also a distinctive aspect of medieval Europe's intolerance, due to its ignorance of such cultures.
Iconoclasm and Iconophobia: Four Historical Case Studies
Authors: Caviness Madeline H.
Published: August 2003

Iconophobia, literally the fear of images, usually occurs in proportion to the powers attributed to images by their believers and attackers. In the worst cases, these fears have led to, or coincide with, a cycle of violence that may involve the actual destruction of images (iconoclasm) and the actual destruction of human life. The distinction between the two activities is often blurred by the language we use: For instance, purging public spaces of the giant statues of Soviet leaders in the early 1990s resonates with the Stalinist purges of living people a generation before (fig. 1). The rhetoric of representation in such photographs of the subjugation and hanging of Lenin('s statue) in Romania in 1990, invokes a retaliation against the real man. The sheer number of such public statues throughout the Soviet Union and its satellites provided many communities with this opportunity for revenge. We also speak of the suppression of imagery, as of popular uprisings; or the eradication of certain beliefs, subjects in art, and even whole tribes of people.
The Emancipation of Thought: On the Work of Michel De Certeau
Authors: Cravetto Maria Letizia
Published: August 2003

Today it seems to be an urgent and necessary task to return to the texts by Michel de Certeau (1925-86). Not because Michel Foucault said of him that he was ‘the best, the brightest of [his] generation’, but for reasons to do with our present thinking.

Indeed, when we consider the social and political disarray of the moment, we are forced to recognize how hard it is, in periods of crisis, to clarify the changes taking place. That implies the emancipation of thought, a process that consists of an inventive interrogation of knowledge and a rigorous elaboration of understanding. This process is one that would not be subject to the dominant ideological models. In addition, thinking of the way clarification and emancipation are intertwined in the most successful intellectual constructions, some of us remember Certeau's work, whose central aim is to clarify the fundamental but stealthy transformations that abruptly emerge into the light of day and undermine the most tenacious assumptions.
`Ivory Lives'
Authors: Nayak Anoop
Published: August 2003

Weaving together historical, structural and cultural approaches to the study of youth, this article examines the impact of global change and economic restructuring in a Northeast English youth community. In breaching the `structural/cultural' divide, the article seeks to intertwine the analysis of cultural identities with local political economy. Using subcultural analysis, the ethnography demonstrates how young people enact `localist', `survivalist' and `globalist' responses to ongoing transformations. As cultural markers of ethnic habitation, these subcultural postures exhibit how youth are imbricated in the making of whiteness in the post-industrial moment. At the same time, the study also illustrates the extent to which contemporary generations can dismantle whiteness to forge transnational new ethnicities, befitting of global times.
Retraditionalizing the Mobile
Authors: Yoon Kyongwon
Published: August 2003

This article, based on ethnographic research in Seoul, South Korea, proposes a `peripheral' and local perspective on teenage mobile phone users and sociality. The teenage users show that the mobile phone, which has often been represented as an example of global imagination technologies, is here appropriated in localized ways in which the traditional form of sociality, Cheong, is rearticulated. After reviewing the recent literature on young people's identity formation in relation to globalization, the article explores the way in which the mobile phone is appropriated as a means of extending traditional sociality between peers and family members. The study suggests that there is no clear-cut evidence that young people have become disembedded from local sociality; rather, they are reimagining the local through global imagination technology.
Negotiating Gender and Personhood in the New South Africa
Authors: Salo Elaine
Published: August 2003

This article examines the shifts in young men's and women's racial and gendered identities in Manenberg, a predominantly coloured, Afrikaans-speaking township in Cape Town, South Africa. It explores how male and female youth destabilizes, renovates and transforms local racial and gendered identities in relation to the local histories, repertoires and ideals of masculinity and femininity and in relation to global cultural forces such as soap operas, rap music and international brand name clothes. Youth obtains access to these global features through electronic media such as television, radio or visits to trendy city nightspots and cosmopolitan beachfront neighbourhoods. This study challenges the idea that cultural flows from the North necessarily lead to cultural hegemonization and homogenization in the South. Instead it suggests that the meanings that these cultural forms assume in this non-western context are shaped by specific local histories and cultural practices.
Youth Culture as Practical Innovation
Authors: Bohnsack Ralf , Nohl Arnd-Michael
Published: August 2003

This article uses extensive qualitative research to address questions about the identifiable peculiarities of adolescence as a phase in the life course. It suggests that the perspective of action theory allows one to see how adolescence is defined through a series of search processes that follow a rationality of their own that is difficult to grasp via utilitarianism. We have called these processes `actionisms'. They evolve within a moratorium (a `time out' that is often initiated by the young people themselves) and are particularly important when young people find themselves deprived of (or liberated from) ties to the local milieu. We suggest that three typical forms of actionist search processes are evident empirically, including forced solidarity within an episodic community of fate, as well as two kinds of alternative milieu formation rooted in either collective or individual identities. This article illustrates the latter process - milieu formation - drawing on our research with young breakdancers of Turkish German origin.
Being Gay, Being Straight and Being Yourself
Authors: Holt Martin , Griffin Christine
Published: August 2003

Authenticity or `being true to the self' continues to be a culturally valued quality despite (or perhaps because of) the increasing fragmentation of identities in contemporary culture. Focusing on accounts of the lesbian and gay `scene' of bars and clubs in Birmingham, UK, we discuss how young people employ a discourse of authenticity when talking about leisure. In our interview material, the scene is privileged as a space to be authentic (somewhere to `be yourself'), particularly for lesbian and gay subjects, but also for heterosexual `visitors'. Through a discursive analysis, we elaborate on the contradictions inherent in these constructions of authentic spaces and identities, widening our discussion to consider how the articulation of authenticity in the local context of Birmingham can be seen as part of a broader discourse of authenticity circulated in an increasingly globalized consumer culture.
Why Action Research?
Authors: Brydon-Miller Mary , Greenwood Davydd , Maguire Patricia
Published: August 2003

Members of the editorial board of Action Research responded to the question, `Why action research?' Based on their responses and the authors' own experiences as action researchers, this article examines common themes and commitments among action researchers as well as exploring areas of disagreement and important avenues for future exploration. We also use this opportunity to welcome readers of this new journal and to introduce them to members of the editorial board.
Action Research and Orders of Democracy
Authors: Gergen Kenneth J.
Published: August 2003

In this article I lay out several premises of a constructionist orientation to action research, as such inquiry contributes to the unfilled hopes for sustaining value and creating new futures. To facilitate these developments a relational orientation to the creation of meaning is outlined, along with implications for revisioning the very idea of democracy. In this context we consider the contribution of action research to two orders of democracy, the first bringing people together into concerted action and the second necessitated by the fragmenting effects of first order democracy. In each case the contributions of action inquiry to a vocabulary of practice are earmarked. Such a vocabulary is now in but a chrysalis stage, but the long-term potentials are substantial.
Feminist Discourses of (Dis)empowerment in an Action Research Project Involving Rural Women and Communication Technologies
Authors: Lennie June , Hatcher Caroline , Morgan Wendy
Published: August 2003

Women's empowerment is a central aim of feminist action research. However, due to the many contradictory discourses of empowerment, it has become a contested concept. Drawing on poststructuralist theories of power-knowledge, discourse and subjectivity, this article critically analyses the discourses identified in an Australian feminist action research project involving rural women, academics and industry partners. This project aimed to empower women to discuss and use interactive communication technologies (ICTs). This analysis highlights the contradictory effects of the egalitarian and expert discourses that were identified, and the multiple, often conflicting, subject positions that were taken up by the researchers and participants. Our analysis suggests that discourses of empowerment and disempowerment intersect and interpenetrate one another, and highlights some of the dangers and contradictions associated with feminist participatory action research. We argue that a poststructuralist approach to analysis and critical reflexivity can lessen the `impossible burden' on academic feminists engaged in emancipatory research.
Pragmatist Philosophy and Action Research
Authors: Reason Peter
Published: August 2003

Richard Rorty's distinct brand of positivism is explored in relation to action research. Rorty's opposition toward the dualisms which haunt western philosophy is briefly described, his nonfoundationalist, anti-metaphysical pragmatics and his views on the contingency of the language that we use outlined. Since we can neither appeal to universal reason nor to an external reality as foundations for our claims, argument must move through a process of redescription. It is argued that just as Rorty is redescribing philosophy, so action researchers are redescribing inquiry. Rorty's ideas are compared with five basic characteristics of action research: practical knowing, democracy and participation; ways of knowing; human and ecological flourishing; and emergent form. Finally, Rorty's notion of the ironist is compared with the action researchers as reflective practitioner. The stimulating quality of Rorty's thought suggests that action researchers must find new language to describe their work, rather than be caught in the old academic metaphors of research.
Fas ligation induces IL-1β-dependent maturation and IL-1β-independent survival of dendritic cells: different roles of ERK and NF-κB signaling pathways
Authors: Guo Zhenhong , Zhang Minghui , An Huazhang , Chen Weilin , Liu Shuxun , Guo Jun , Yu Yizhi , Cao Xuetao
Published: August 2003

The mechanisms that underpin the intriguing capacity of Fas ligation on dendritic cells (DCs) to induce maturation and activation, rather than apoptosis, remain unclear. In the present study we confirm that Fas signaling induces both phenotypic and functional maturation of murine DCs, and we demonstrate that phenotypic maturation is associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, activation of caspase-1, and secretion of interleukin-β (IL-1β). Specific inhibition of ERK1/2 diminished Fas ligation-induced caspase-1 activation, IL-1β secretion, and ensuing up-regulation of developmental markers, whereas treatment with neutralizing anti-IL-1β antibody abrogated phenotypic and functional maturation, indicating that IL-1β mediates Fas ligation-induced DC maturation in an autocrine manner. NF-κB activation was responsible for maintaining DC viability after Fas ligation. Inhibiting NF-κB did not affect either IL-1β secretion or phenotypic maturation but rather sensitized DCs to Fas-mediated apoptosis. In conclusion, positive signals originating from Fas are transduced through at least 2 different intracellular pathways in DCs, promoting not only survival but also an increase in maturation that correlates with increased antigen-presentation capability. (Blood. 2003;102:4441-4447)
Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin
Authors: Reiter Rosemarie A. , Mayr Florian , Blazicek Hannes , Galehr Elisabeth , Jilma-Stohlawetz Petra , Domanovits Hans , Jilma Bernd
Published: August 2003

Whereas bleeding is the most frequent adverse event encountered in patients receiving glycoprotein (GP) IIb/IIIa inhibitors, there are currently no recommendations for how to treat such patients. The present study tested the hypothesis that infusion of desmopressin (DDAVP) reverses the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin). Study group 1 (10 healthy volunteers) received a DDAVP infusion to establish dose-response curves for the in vitro inhibition of platelet function by eptifibatide, abciximab, and tirofiban together with l-aspirin before and after DDAVP. In a randomized, double-blind, placebo-controlled, crossover study (group 2) volunteers received l-aspirin and a standard eptifibatide infusion. Thereafter, DDAVP or a physiologic saline infusion was given over 30 minutes. In group 1, all GPIIb/IIIa inhibitors prolonged collagen-epinephrine (CEPI) and collagen-adenosine diphosphate (CADP) closure times (CTs), measured with the platelet function analyzer 100 (PFA-100). DDAVP caused a shift in the concentration response curves to the right of all 3 GPIIb/IIIa inhibitors. In group 2, DDAVP accelerated the normalization of CADP-CT and CEPI-CT after the stop of eptifibatide infusion with a maximum effect at 1.5 hours to 2 hours. In contrast, CEPI-CT remained above normal in the placebo group for more than 4 hours. In conclusion, DDAVP accelerates normalization of the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin). (Blood. 2003;102:4594-4599)
Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia
Authors: Holleman Amy , Boer Monique L. den , Kazemier Karin M. , Janka-Schaub Gritta E. , Pieters Rob
Published: August 2003

Resistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in leukemic cells from 50 children with ALL was studied after in vitro exposure with 4 important drugs in ALL therapy (prednisolone, vincristine, l-asparaginase, and daunorubicin). Exposure to each drug resulted in early induction of phosphatidylserine (PS) externalization and mitochondrial transmembrane (Δψm) depolarization followed by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) inactivation in the majority of patients. For all 4 drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalization (< .001 < P < .008) and (2) the percentage of cells with Δψm depolarization (.002 < P < .02). However, the percentage of cells with caspase-3 activation and the percentage of cells with PARP inactivation showed a significant inverse correlation with cellular resistance for prednisolone (P = .001; P = .001) and l-asparaginase (P = .01; P = .001) only. This suggests that caspase-3 activation and PARP inactivation are not essential for vincristine- and daunorubicin-induced apoptosis. In conclusion, resistance to 4 unrelated drugs is associated with defect(s) upstream or at the level of PS externalization and Δψm depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL. (Blood. 2003;102:4541-4546)
Monocyte-expressed urokinase inhibits vascular smooth muscle cell growth by activating Stat1
Authors: Kunigal Sateesh , Kusch Angelika , Tkachuk Natalia , Tkachuk Sergey , Jerke Uwe , Haller Hermann , Dumler Inna
Published: August 2003

After vascular injury, a remodeling process occurs that features leukocyte migration and infiltration. Loss of endothelial integrity allows the leukocytes to interact with vascular smooth muscle cells (VSMCs) and to elicit “marching orders”; however, the signaling processes are poorly understood. We found that human monocytes inhibit VSMC proliferation and induce a migratory potential. The monocytes signal the VSMCs through the urokinase-type plasminogen activator (uPA). The VSMC uPA receptor (uPAR) receives the signal and activates the transcription factor Stat1 that, in turn, mediates the antiproliferative effects. These results provide the first evidence that monocytes signal VSMCs by mechanisms involving the fibrinolytic system, and they imply an important link between the uPA/uPAR-related signaling machinery and human vascular disease. (Blood. 2003;102: 4377-4383)
Induction of human γ globin gene expression by histone deacetylase inhibitors
Authors: Cao Hua , Stamatoyannopoulos George , Jung Manfred
Published: August 2003

We investigated the induction of human γ globin gene activity by 3 classes of histone deacetylase inhibitors: amide analogues of trichostatin A, hydroxamic acid analogues of trapoxin, and scriptaid and its analogues. The screening consisted of measuring the effects of these compounds on γ and β human gene promoter activity by using cultures of GM979 cells stably transfected with a construct containing a γ promoter linked to firefly luciferase and a β promoter linked to renilla luciferase. Compounds belonging to all 3 classes induced γ gene promoter activity in the screening assay in low micromolar concentrations. Histone deacetylase (HDAC) inhibitors increased acetylation of histone H4 and induced the expression of endogenous murine embryonic genes. They also increased the levels of γ mRNA and the frequency of fetal hemoglobin-containing erythroblasts in erythroid burst-forming unit (BFUe) cultures from healthy adult individuals. Compounds that displayed very similar degrees of inhibition of the HDAC activity in an HDAC enzymatic assay differed strikingly on their effects on γ gene promoter activity, raising the possibility of selectivity of HDACs that interact with the γ globin gene chromatin.
Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells
Authors: Chandra Joya , Hackbarth Jennifer , Le Son , Loegering David , Bone Nancy , Bruzek Laura M. , Narayanan Ven L. , Adjei Alex A. , Kay Neil E. , Tefferi Ayalew , Karp Judith E. , Sausville Edward A. , Kaufmann Scott H.
Published: August 2003

Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. (Blood. 2003;102:4512-4519)
Role of AP1/NFE2 binding sites in endogenous α-globin gene transcription
Authors: Loyd Melanie R. , Okamoto Yasuhiro , Randall Mindy S. , Ney Paul A.
Published: August 2003

High-level α-globin expression depends on cis-acting regulatory sequences located far upstream of the α-globin cluster. Sequences that contain the α-globin positive regulatory element (PRE) activate α-globin expression in transgenic mice. The α-globin PRE contains a pair of composite binding sites for the transcription factors activating protein 1 and nuclear factor erythroid 2 (AP1/NFE2). To determine the role of these binding sites in α-globin gene transcription, we mutated the AP1/NFE2 sites in the α-globin PRE in mice. We replaced the AP1/NFE2 sites with a neomycin resistance gene (neo) that is flanked by LoxP sites (floxed). Mice with this mutation exhibited increased embryonic death and α-thalassemia intermedia. Next, we removed the neo gene by Cre-mediated recombination, leaving a single LoxP site in place of the AP1/NFE2 sites. These mice were phenotypically normal. However, α-globin expression, measured by allele-specific RNA polymerase chain reaction (PCR), was decreased 25%. We examined the role of the hematopoietic-restricted transcription factor p45Nfe2 in activating expression through these sites and found that it is not required. Thus, we have demonstrated that AP1/NFE2 binding sites in the murine α-globin PRE contribute to long-range α-globin gene activation. The proteins that mediate this effect remain to be determined. (Blood. 2003;102:4223-4228)
Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy
Authors: Lancet Jeffrey E. , Karp Judith E.
Published: August 2003

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
Matrix-fibrinogen enhances wound closure by increasing both cell proliferation and migration
Authors: Rybarczyk Brian J. , Lawrence Sarah O. , Simpson-Haidaris Patricia J.
Published: August 2003

Fibrinogen (FBG) assembles into matrix fibrils of fibroblasts, lung and mammary epithelial cells, but not endothelial cells. Furthermore, cryptic β15-21 residues are exposed in FBG fibrils with no evidence of thrombin or plasmin proteolysis. Herein, the effects of FBG on migration and proliferation of wounded dermal fibroblasts were investigated. FBG preassembled into matrix prior to scrape-wounding induced 3H-thymidine incorporation 8-fold and shortened the time to wound closure 1.6-fold ± 0.1-fold. FBG added immediately after wounding did not enhance either response. Fibroblast growth factor-2/platelet-derived growth factor (FGF-2/PDGF) stimulated cell proliferation 2.2-fold for FGF-2 and 3.2-fold for PDGF and wound closure 1.5-fold ± 0.1-fold in the absence of matrix-FBG. Surprisingly, exogenous growth factors had negligible effect on wound closure and cell proliferation already enhanced by matrix-FBG. Matrix-FBG-enhanced wound closure required active assembly of an FBG-fibronectin matrix, engagement of αvβ3, and FBG Aα-RGDS572-575 integrin recognition sites; Aα-RGDF95-98 sites were not sufficient for matrix-FBG assembly, enhanced wound closure, or cell proliferation. Although Bβ1-42 was not necessary for matrix assembly, it was required for matrix-FBG-enhanced cell migration. These data indicate that FBG serves as an important matrix constituent in the absence of fibrin formation to enhance wound repair and implicate Bβ1-42 as a physiologic inducer of signal transduction to promote an intermediate state of cell adhesion and a migratory cell phenotype. (Blood. 2003;102:4035-4043)
Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity
Authors: Tellam Judy , Connolly Geoff , Webb Natasha , Duraiswamy Jaikumar , Khanna Rajiv
Published: August 2003

The ability of viral or mutated cellular oncogenes to initiate neoplastic events and their poor immunogenicity have considerably undermined their potential use as immunotherapeutic tools for the treatment of human cancers. Using an Epstein-Barr virus-encoded oncogene, latent membrane protein 1 (LMP1), as a model, we report a novel strategy that both deactivates cellular signaling pathways associated with the oncogenic phenotype and reverses poor immunogenicity. We show that cotranslational ubiquitination combined with N-end rule targeting of LMP1 enhanced the intracellular degradation of LMP1 and total blockade of LMP1-mediated nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) activation in human cells. In addition, although murine cells expressing LMP1 were uniformly tumorigenic, this oncogenicity was completely abrogated by covalent linkage of LMP1 with ubiquitin, while an enhanced CD8+ T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1. These observations suggest that proteasomal targeting of tumor-associated oncogenes could be exploited therapeutically by either gene therapy or vaccination. (Blood. 2003;102:4535-4540)
Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines
Authors: Chung Hye-Kyung , Young Howard A. , Goon Peter K. C. , Heidecker Gisela , Princler Gerald L. , Shimozato Osamu , Taylor Graham P. , Bangham Charles R. M. , Derse David
Published: August 2003

Human T-cell leukemia virus type 1 (HTLV-1) infection profoundly alters T-cell gene expression, and the dysregulated synthesis of cytokines could influence the course and pathologic consequences of infection. In the process of screening T-cell lines for T helper 1 (Th1) and Th2 cytokine mRNAs, we observed that interleukin-13 (IL-13) mRNA was highly expressed in HTLV-1-infected, IL-2-dependent T-cell lines. IL-9 and interferon gamma (IFN-γ) mRNAs were also expressed at high levels in chronically infected cell lines. IL-5 mRNA was detected in 60% of the HTLV-1-infected cell lines, but mRNAs for IL-4, IL-10, IL-2, and IL-15 were either below detection limits or did not correlate with HTLV-1 infection. Transcriptional activation of the IL-13 promoter by the HTLV-1 Tax trans-regulatory protein was demonstrated in Jurkat T cells transiently transfected with an IL-13 promoter-reporter plasmid. The clinical relevance of these observations was demonstrated by immunofluorescent staining and flow cytometry of lymphocytes obtained from HTLV-1-infected patients. These studies revealed that IL-13 production was directly related to the level of Tax expression in the infected CD4+ T cells soon after in vitro culture. As IL-13 plays key roles in tumor immunosurveillance, asthma, and central nervous system inflammation, it may contribute to the pathophysiology of HTLV-1-associated diseases. (Blood. 2003;102:4130-4136)
Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation
Authors: Dorfleutner Andrea , Ruf Wolfram
Published: August 2003

The tissue factor (TF)–initiated coagulation pathway plays important roles in hemostasis, inflammation, metastasis, and angiogenesis. Phosphorylation of the TF cytoplasmic domain is functionally relevant in metastasis. How TF cytoplasmic domain phosphorylation downstream of protein kinase C (PKC) activation is regulated in primary vascular cells remains poorly understood. Here, phosphorylation of Ser258, rather than the PKC consensus site Ser253, is identified as the major conformational switch required for recognition by a phosphorylation-specific antibody. With this novel reagent, we demonstrate that the TF cytoplasmic domain is primarily unphosphorylated in confluent endothelial cells. TF cytoplasmic domain phosphorylation can occur in the absence of the autologous TF transmembrane and extracellular domains but requires maturation of TF in the Golgi compartment and cell surface expression. Site-directed mutagenesis and 2-bromopalmitate treatment provide evidence that palmitoylation of the cytoplasmic Cys245 is a negative regulatory mechanism of Ser258 phosphorylation. Profiling with PKC-selective inhibitors identifies PKCα as important for TF cytoplasmic domain phosphorylation. Mutagenesis of protein kinase consensus sites are consistent with a model in which PKC-dependent phosphorylation of Ser253 enhances subsequent Ser258 phosphorylation by a Pro-directed kinase. Thus, cell surface location–dependent phosphorylation of the TF cytoplasmic domain is regulated at multiple levels.
PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells
Authors: Xu Ming-jiang , Sui Xingwei , Zhao Runxiang , Dai Chunhua , Krantz Sanford B. , Zhao Zhizhuang Joe
Published: August 2003

Polycythemia vera (PV) is a human clonal hematologic disorder. Previously we demonstrated that erythroid colony-forming cells (ECFCs) from PV patients contained a hyperactive membrane-associated tyrosine phosphatase. We now show that this phosphatase corresponded to protein tyrosine phosphatase (PTP)-MEG2, an intracellular enzyme with a putative lipid-binding domain. The increased activity of PTP-MEG2 in PV cells is due to its elevated distribution in the membrane fraction. With the development of ECFCs to mature red cells, the protein level of PTP-MEG2 decreased gradually, but membrane-associated PTP-MEG2 was sustained for a longer period of time in PV cells, which correlated with an enhanced colony-forming capability of the cells. Importantly, expression of dominant-negative mutant forms of PTP-MEG2 suppressed in vitro growth and expansion of both normal and PV ECFCs. The data indicate that PTP-MEG2 has an important role in the development of erythroid cells. (Blood. 2003;102:4354-4360)
Developmental stage–specific epigenetic control of human β-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation
Authors: Bottardi Stefania , Aumont Angélique , Grosveld Frank , Milot Eric
Published: August 2003

To study epigenetic regulation of the human β-globin locus during hematopoiesis, we investigated patterns of histone modification and chromatin accessibility along this locus in hematopoietic progenitor cells (HPCs) derived from both humans and transgenic mice. We demonstrate that the developmentally related activation of human β-like globin genes in humans and transgenic mice HPCs is preceded by a wave of gene-specific histone H3 hyperacetylation and K4 dimethylation. In erythroid cells, expression of β-like globin genes is associated with histone hyperacetylation along these genes and, surprisingly, with local deacetylation at active promoters. We also show that endogenous mouse β major and human β-like genes are subject to different epigenetic control mechanisms in HPCs. This difference is likely due to intrinsic properties of the human β-globin locus since, in transgenic mice, this locus is epigenetically regulated in the same manner as in human HPCs. Our results suggest that a defined pattern of histone H3 acetylation/dimethylation is important for specific activation of human globin promoters during development in human and transgenic HPCs. We propose that this transient acetylation/dimethylation is involved in gene-specific potentiation in HPCs (ie, before extensive chromatin remodeling and transcription take place in erythroid cells).
BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis
Authors: Tsai Peter T. , Lee Robert A. , Wu Hong
Published: August 2003

Thymocyte development is a non–cell-autonomous process that requires signals provided by the thymic stroma. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) derived from thymic stroma have been implicated as possible regulators of T-cell development. Using thymic organ culture, this study demonstrates that both BMP4 and FGF7/FGF10 arrest early T-cell development at the CD4-CD8-CD44+CD25- (double-negative 1 [DN1]) population and at the CD4-CD8- double-negative (DN) to CD4+CD8+ double-positive (DP) transition in a stromal compartment–dependent manner. Furthermore, BMP4 functions upstream of FGF7/FGF10, as the effects of BMP can be suppressed by cotreatment with an FGF receptor antagonist. BMP4 also acts directly on the thymic stroma to up-regulate the stroma-specific transcription factor Foxn1 and stroma-expressed chemokines. Taken together, the data in this report demonstrate that BMP acts upstream of FGF in the regulation of early T-cell development and that BMP4 acts primarily through the thymic stroma, thereby altering the thymic microenvironment and affecting thymopoiesis.
Specific abrogation of transforming growth factor-β signaling in T cells alters atherosclerotic lesion size and composition in mice
Authors: Gojova Andrea , Brun Valérie , Esposito Bruno , Cottrez Françoise , Gourdy Pierre , Ardouin Patrice , Tedgui Alain , Mallat Ziad , Groux Hervé
Published: August 2003

A large body of evidence supports a role for proinflammatory mediators in atherosclerotic disease progression and instability. However, only few endogenous mechanisms have been suggested that could alter disease progression. One such mechanism is thought to be mediated by transforming growth factor β (TGF-β). Transgenic mice that express a dominant-negative TGF-β receptor type II under a T-cell-specific promoter were generated. Bone marrow transplantation from transgenic mice into irradiated low density lipoprotein receptor knock-out (LDLr KO) mice, subsequently fed an atherogenic diet, resulted in T-cell-specific blockade of TGF-β signaling in the recipient mice and increased differentiation of T cells toward both T helper 1 (Th1) and Th2 phenotypes. These mice showed a significant decrease in atherosclerotic lesion size in the aortic sinus compared with mice receiving transplants with the wild-type bone marrow. Atherosclerotic plaques of mice receiving transplants with the transgenic bone marrow showed increased T-cell infiltration and expression of major histocompatability complex (MHC) class II, along with a decrease in smooth muscle cell and collagen content, a plaque phenotype that is potentially vulnerable to rupture. These results identify for the first time an important role for specific and selective T-cell-TGF-β signaling in atherosclerosis. (Blood. 2003;102:4052-4058)
Production of functional platelets by differentiated embryonic stem (ES) cells in vitro
Authors: Fujimoto Tetsuro-Takahiro , Kohata Satoshi , Suzuki Hidenori , Miyazaki Hiroshi , Fujimura Kingo
Published: August 2003

Megakaryocytes and functional platelets were generated in vitro from murine embryonic stem (ES) cells with the use of a coculture system with stromal cells. Two morphologically distinctive megakaryocytes were observed sequentially. Small megakaryocytes rapidly produced proplatelets on day 8 of the differentiation, and large hyperploid megakaryocytes developed after day 12, suggesting primitive and definitive megakaryopoiesis. Two waves of platelet production were consistently observed in the culture medium. A larger number of platelets was produced in the second wave; 104 ES cells produced up to 108 platelets. By transmission electron microscopy, platelets from the first wave were relatively rounder with a limited number of granules, but platelets from the second wave were discoid shaped with well-developed granules that were indistinguishable from peripheral blood platelets. ES-derived platelets were functional since they bound fibrinogen, formed aggregates, expressed P-selectin upon stimulation, and fully spread on immobilized fibrinogen. These results show the potential utility of ES-derived platelets for clinical applications. Furthermore, production of gene-transferred platelets was achieved by differentiating ES cells that were transfected with genes of interest. Overexpression of the cytoplasmic domain of integrin β3 in the ES-derived platelets prevented the activation of αIIbβ3, demonstrating that this system will facilitate functional platelet studies. (Blood. 2003;102:4044-4051)