bluuebunny/crossref_metadata_2025 huggingface dataset:
Before UNESCO and the WHO
Authors: Ghebali Victor-Yves
Published: November 2002

Jean-Jacques Renoliet, L'UNESCO oubliée. La Société des Nations et la coopération intellectuelle (1919–1946), foreword by René Girault (Paris: Publications de la Sorbonne, 1999), 352 pp., FF180, ISBN 2-6384-7701-1.

Christel Taillibert, L'Institut international du cinématographe international éducatif. Regards sur le rôle du cinéma éducatif dans la politique internationale du fascisme italien (Paris: L'Harmattan, 1999), 401 pp., FF180, ISBN 2-85944-384-3.

Marta Aleksandra Balińska, Une vie pour l'humanitaire. Ludwik Rajchmann, 1881–1965, foreword by Bronislaw Geremek, L'Espace de l'histoire (Paris: La Découverte, 1995), 399 pp., FF165, ISBN 2-7071-2485-0.
Parliamentary Representation in Europe: Past, Present, and Future
Authors: Gabel Matthew
Published: November 2002

Richard Katz and Bernhard Wessels, eds., The European Parliament, the National Parliaments, and European Integration (New York: Oxford University Press, 1999), 280pp., £35, h.b., ISBN 0-19-829660-6.

Heinrich Best and Maurizio Cotta, eds., Parliamentary Representatives in Europe, 1848–2000 (Oxford and New York: Oxford University Press 2000), 530pp., £55, h.b., ISBN 0-19-829793-9.

Jean Blondel, Richard Sinnott and Palle Svensson, People and Parliament in the European Union. Participation, Democracy, and Legitimacy (Oxford: Clarendon Press, 1998), 287pp., £45, h.b., ISBN 0-19-829308-9.

Amie Kreppel, The European Parliament and Supranational Party System. A Study in Institutional Development (Cambridge: Cambridge University Press, 2001), 288pp., £40, h.b., ISBN 0-521-80625-9.
AN INVESTIGATION OF THE RELATIONSHIP BETWEEN RESPONSIBILITY AND ATTENTION DEFICITS CHARACTERISTIC OF OBSESSIVE-COMPULSIVE PHENOMENA
Authors: Pleva Jessica , Wade Tracey D.
Published: November 2002

Attention deficits and inflated perceptions of responsibility have been identified as characteristics of people with obsessive-compulsive disorder (OCD). The present study examined the relative importance of responsibility and attention in predicting non-clinical levels of obsessionality. Three hundred Australian university students were screened using the Maudsley Obsessional-Compulsive Inventory (MOCI), and students who scored in the top and bottom 10% of the distribution were selected for participation. The selected participants completed the Responsibility Attitude Scale (RAS) and the Test of Everyday Attention (TEA), along with measures of trait-anxiety and depression. High MOCI scorers exhibited a greater perception of responsibility, and poorer overall attention than low MOCI scorers. These differences remained significant after controlling for trait-anxiety and depression. Logistic regression analyses revealed that responsibility was a stronger predictor of non-clinical obsessionality than was attention. Moreover, attention did not make a significant contribution to the prediction of obsessionality once responsibility had been controlled. Correlations between responsibility and TEA visual selective attention subtests remained significant after controlling for obsessionality. These findings suggest that measures of attention (particularly measures of visual selective attention) may be confounded by responsibility attitudes, thus highlighting the importance of controlling for meta-cognitive variables such as responsibility when investigating attention in OCD.
THE ROLE OF MEMORY PERSPECTIVE IN SOCIAL PHOBIA: IMMEDIATE AND DELAYED MEMORIES FOR ROLE-PLAYED SITUATIONS
Authors: Coles Meredith E. , Turk Cynthia L. , Heimberg Richard G.
Published: November 2002

Cognitive-behavioral models (Clark & Wells, 1995; Rapee & Heimberg, 1997) and recent research suggest that individuals with social phobia (SP) experience both images (Hackmann, Surawy, & Clark, 1998) and memories (Coles, Turk, Heimberg, & Fresco, 2001; Wells, Clark, & Ahmad, 1998) of anxiety-producing social situations from an observer perspective. The current study examines memory perspective for two role-played situations (speech and social interaction) at multiple time points (immediate and 3 weeks post) in 22 individuals with generalized SP and 30 non-anxious controls (NACs). At both time points, SPs recalled the role-plays from a more observer/less field perspective than did NACs. Further, over time, the memory perspective of SPs became even more observer/less field while the memory perspective of NAC remained relatively stable.
THE SOCIAL BASIS OF WORRY IN THREE SAMPLES: HIGH-SCHOOL STUDENTS, UNIVERSITY STUDENTS, AND OLDER ADULTS
Authors: Ladouceur Robert , Freeston Mark H. , Fournier Sarah , Dugas Michel J. , Doucet Céline
Published: November 2002

Comorbidity data between Generalized Anxiety Disorder (GAD) and Social Phobia, studies of frequently reported worry themes, and various correlational studies have led to the idea that worries may have a social basis. This study investigates the social basis of worry in three samples with different ages. The samples consisted of 224 high-school students, 607 undergraduate students, and 125 older adults. All participants completed the Worry Domains Questionnaire (WDQ) and the Penn State Worry Questionnaire (PSWQ). We hypothesized that for each sample, the first factor extracted following factor analysis on WDQ items would reflect the most social content, and that social-related factors would be the best predictors of the global tendency to worry as measured by the PSWQ. Results supported the hypotheses with the exception of older adults, for whom the first extracted factor was not as obviously social as for the other two samples. Possible explanations are considered and theoretical and clinical implications are discussed.
OPTIMAL AND NORMAL AFFECT BALANCE IN PSYCHOTHERAPY OF MAJOR DEPRESSION: EVALUATION OF THE BALANCED STATES OF MIND MODEL
Authors: Schwartz Robert M. , Reynolds III Charles F. , Thase Michael E. , Frank Ellen , Fasiczka Amy L. , Haaga David A. F.
Published: November 2002

The reformulated balanced states of mind (BSOM) model (Schwartz, 1997) proposed new cognitive-affective set-point ratios based on a mathematical model of consciousness (Lefebvre, 1990) to differentiate among pathological, normal and optimal balances. Using data derived from the Affects Balance Scale (Derogatis, 1975), the reformulated set-points were empirically evaluated by tracking changes in affect balance SOM (ratio of positive to total affect) in 66 depressed male outpatients undergoing cognitive-behavior therapy (n = 45) or pharmacotherapy (n = 21). Confidence interval estimations indicated that across treatments both remitted (SOM = .35) and unremitted (SOM = .35) patients had pathological pretreatment affect balances near the predicted set-point (.38). At post-treatment, affect balance for remitted patients (SOM = .74) progressed to a normal dialogue near the predicted set-point (.72), whereas unremitted patients maintained a negative balance (SOM = .41). Using Hamilton and Global Assessment Scale ratings, remitted patients were classified into average and optimal responders. At post-treatment, average responders achieved an affect balance (SOM = .70) near the normal dialogue set-point (.72), whereas optimal responders progressed to an affect balance (SOM = .81) at the optimal dialogue set-point (.81), supporting the theoretical distinction between normal and optimal balance. A mathematically generated measure that distinguishes normality and optimality permits increased quantitative precision in comparative psychotherapy outcome research.
CHANGING STAFF ATTITUDES AND EMPATHY FOR WORKING WITH PEOPLE WITH PSYCHOSIS
Authors: McLeod Hamish J. , Deane Frank P. , Hogbin Bruce
Published: November 2002

Seventy-seven mental health professionals completed a 3-day cognitive behavioural training course for managing hallucinations and delusions in schizophrenia. A questionnaire measuring attitudes and empathy towards working with people who have these symptoms was administered before and after the course. Significant increases in feelings of adequacy, legitimacy, employment related self-esteem, and expectations of work satisfaction were observed after the course and participants displayed high levels of motivation for working with this clinical population at both time points. In addition, the participants showed significant increases in perceived empathy for the experience of hallucinations and delusions. This was a predicted outcome as the course included exercises designed to enhance therapists' understanding of the subjective experience of psychotic symptoms. Empathy is recognized in the wider psychotherapy outcome literature as a therapeutically important variable that influences the formation of a therapeutic alliance but it is a relatively unexamined construct in CBT for psychosis. Further investigations in this area will potentially enhance psychological treatment delivery and subsequent outcomes for people who experience hallucinations and delusions. Furthermore, explication of such “non-specific” therapeutic factors may help to explain some of the transient but beneficial effects of unstructured “control” therapies observed in recent CBT for psychosis outcome trials.
CLINICAL SUPERVISION IN PRACTICE: A SURVEY OF UK COGNITIVE BEHAVIOURAL PSYCHOTHERAPISTS ACCREDITED BY THE BABCP
Authors: Townend Michael , Iannetta Louise , Freeston Mark H.
Published: November 2002

Clinical supervision is an integral aspect of training and is essential for accreditation as a cognitive behavioural psychotherapist. A questionnaire survey of a random sample of accredited British Association of Behavioural and Cognitive Psychotherapists (n = 280) is reported, 61% (N = 170) responded by describing their supervision practices in a number of areas. These included the organization of supervision, content, satisfaction, techniques, models, interdisciplinary working and supervision of others. The results indicate that satisfaction levels with supervision were high amongst accredited therapists and that the ratio of time spent in supervision to therapeutic contact is, on average, higher than recommended minimum levels. Supervision was less structured and active than therapy and little use was made of audio/video tapes of therapy sessions within supervision. The level of training for supervisors was highly variable with a substantial proportion having received no formal training in cognitive behavioural psychotherapy supervision. Dual role relationships were also common. Finally, recommendations for further research and practice are made.
Historical Representations of Yaʿqūb b. al-Layth: A Reappraisal
Authors: Tor D. G.
Published: November 2002

The extraordinary ascendancy of the Saffarid dynasty began with the meteoric career of its founder, Yaʿqūb b. al-Layth al-Saffār. Yaʿqūb appeared on the historical scene in 238/852 as the member of an Eastern Iranian military band, and ended his days as the ruler over a vast swathe of territory stretching from today's ʿIraq to the borders of today's India; while at least theoretical acknowledgement of his overlordship was found both in Central Asia and the holy cities of Arabia.
The 1934 Chinese Mission to Tibet: A Re-examination
Authors: Lin Hsiao-Ting
Published: November 2002

In the spring of 1934, a Chinese mission led by General Huang Musong, then Deputy Chief of the General Staff of the Guomindang regime, was dispatched to Lhasa with the official purpose of offering condolences to the late 13th Dalai Lama who died in late 1933. Huang's visit to Tibet undoubtedly was the most politically symbolic event in Sino-Tibetan relations since the collapse of the Qing dynasty. He became the most high-profile of Chinese officials to have entered Lhasa since 1911, when the Chinese Republic was created. Before returning to Nanking, Huang left a representative office, along with a wireless set in Lhasa; these could be actions which the Chinese considered marked their authority in Tibet.
Project Work in Context: Regulatory Change and the New Geography of Media
Authors: Christopherson Susan
Published: November 2002

Like all forms of work, project work is constructed within the rules that govern labor and capital markets. In this paper, I examine how project work and the project workforce in ‘old’ media (motion pictures and television) and ‘new’ media (multimedia or Internet-based information, entertainment, and infotainment) have been affected by changes in the regulatory regime governing entertainment and information-intensive industries in the United States. Of particular significance is the role that collective bargaining institutions play in industry governance. In the case of old media, the regulatory regime initiated in the 1980s by the Reagan administration considerably reshaped the terrain for media production. ‘Virtual integration’ of a substantial portion of production resulted in the routinization of project work and decreased the need for collocation of preproduction, production, and postproduction in Los Angeles, the ‘home base’ of these industries. Old media, however, retained the key governance organizations that predated changes in regulation, particularly guilds and unions. New media, by contrast, emerged in the 1990s era of laissez-faire regulatory policy. ‘Consent decrees’, regulating competition in a wide range of industries were lifted, allowing firms to acquire, merge, and move freely both to concentrate economic power and to diversify. Unlike their old-media counterparts, new-media workers (and their employers) did not have the intermediary institutions to set the rules for employment, to define roles in project production, or to facilitate project management. For the new-media worker, and his or her employers, stronger dependence on interpersonal connections for credentials, legitimacy, and job match means stronger dependence on regional markets. The history of change and continuity in media project work can illuminate broader questions, such as how market regulation affects the location strategies of firms and workers.
Distributing Intelligence and Organizing Diversity in New-Media Projects
Authors: Girard Monique , Stark David
Published: November 2002

In this paper we examine how web-design firms in the new-media industry probe and experiment with possible forms and sources of value that give shape to the new economy. Focusing on the collaborative engineering of cross-disciplinary web-design project teams, we examine how websites emerge as provisional settlements among heterogeneous disciplines as they negotiate working compromises across competing performance criteria.
Shifting New Media: From Content to Consultancy, from Heterarchy to Hierarchy
Authors: Lash Scott , Wittel Andreas
Published: November 2002

This is a detailed case history of one of London's iconic new-media companies, AMX Studios. Some of the changes in this firm, we assume, are not atypical for other firms in this sector. In particular we want to draw attention to two transformations. The first change in AMX and in London's new-media industry more generally refers to the field of industrial relations. What can be observed is a shift from a rather heterarchically organised new-media industry towards a more hierarchically organised one, a shift from short-term project networks to long-term client dependency. The second change refers to new-media products and services. We want to argue for a shift from cool content production towards consultancy and interactive communications solutions.
Examining Distance Effects on Hospitalizations Using GIS: A Study of Three Health Regions in British Columbia, Canada
Authors: Lin Ge , Allan Diane E , Penning Margaret J
Published: November 2002

We examine travel distance and its effect on total and on avoidable hospitalizations, using data from three health regions in British Columbia, Canada. We conceptualize distance to hospital in geographic and socioeconomic contexts from the care seeker's perspective, and develop a GIS procedure to generate variables for these contexts. The procedure includes geocoding hospital locations and patient locations to determine travel distance for each hospitalization, generating several geographic barriers such as mountain crossings, and linking patient-neighborhood locations to socioeconomic variables. The findings reveal that overall, hospitalization rates are inversely related to distance to hospital. Even though low-income patients are more likely to be hospitalized for avoidable conditions, the income effect influences different dimensions from those affected by the distance effect. A balanced approach may be needed to address issues appropriately at both the low and the high ends of physical accessibility.
The State, Skilled Labour Markets, and Immigration: The Case of Doctors in England
Authors: Raghuram Parvati , Kofman Eleonore
Published: November 2002

Most recent research on skilled migration focuses on those working in the financial sectors and there has been very little work in Europe on the migration of people in welfare sectors. In this paper we seek to explore some of the complexities of shifting labour markets and immigration regulations and their influence on the geography of migration of doctors to England. We argue that state regulations, both of immigration and those governing the medical labour force, have been altered to meet the specificities of internal labour-market shortages and that the level of the state remains a useful analytical level for understanding the skilled migration of doctors.
European Integration and the Spatial Dynamics of Manufacturing-Employment Change
Authors: Melachroinos Konstantinos A
Published: November 2002

The author examines the dynamics of manufacturing-employment change in thirteen European Union countries between 1978 and 1996, mainly through the utilisation of shift-share techniques. Despite the momentum that European integration gained over this period, the key finding is that the geography of manufacturing employment has remained almost intact. Processes operating at the European scale appear to have the largest impact on labour outcomes in each member state, while there is little deviation from the widespread declining trends. Spatial stability is reinforced even further through the homogeneity of several national industrial structures. In addition, the moderate increase in the industrial specialisation of the participating economies, and the localisation tendencies of a few traditional subsectors, pose little if any threat to the stability of the present map of manufacturing distribution. This evidence suggests that, contrary to some political rhetoric, the integration process has not, so far at least, adversely affected the relative competitiveness of manufacturing either in peripheral or in core countries.
Constructing Innovativeness in New-Media Start-Up Firms
Authors: Heydebrand Wolf , Mirón Annalisa
Published: November 2002

We focus on the social construction of innovativeness in the context of project teams and interfirm networks among new-media start-up firms in Silicon Alley, Manhattan. The analysis is based on a total of thirty-four interviews with firm executives and other informants. A brief discussion of the historical and structural context of the research project is followed by an exposition of the theoretical framework, that is, the theory of industrial districts and the hypothesized connection between innovativeness and interactivity. In each of the three subsequent sections of the paper, the empirical findings are presented and analyzed: the grounded conceptions of innovativeness, the two main variants of project organization (self-organized versus managerially coordinated project teams), and the varieties of interfirm networks such as transactional and mixed networks. Other networking practices documented are client relations and hiring. We consider the effect of state-level legal infrastructure and economic deregulation on the business culture of interfirm networking, information sharing, and innovativeness.
A Comparison of the Effects of Differences in Temporal Gating and Ear of Presentation on Profile Discrimination
Authors: Hill Nicholas I , Bailey Peter J
Published: November 2002

The aim of the study was to examine the effects of differences in temporal gating and ear of presentation (both separately and in combination) on listeners' ability to detect an increment in the level of a 1 kHz component (the target) relative to that of four spectrally flanking components. The flanking components were always presented to the listeners' right ear, while the target component was either presented to the same ear (monaural presentation) or to the left ear (dichotic presentation). Similarly, the target and flanking components were either gated on and off at the same time (synchronous presentation), or else the target component began 100 ms before and terminated 100 ms after the four flanking components (asynchronous presentation). On average, thresholds were lowest in the synchronous, monaural condition, and highest in the two asynchronous conditions. Ear differences alone did result in elevated thresholds for most listeners. However, combining differences in gating and ear of presentation produced thresholds that were indistinguishable from those obtained when gating differences alone were employed. These results are consistent with the suggestion that differences in temporal gating lead to more complete segregation of concurrent frequency components than differences in spatial location.
The Eyes Have it: A Perceptual Investigation of Eyespots
Authors: Dziurawiec Suzanne , Deręgowski Jan B
Published: November 2002

Previous work with non-human species has shown that eyespots function as sign stimuli for defensive behaviour. But it is unknown to what extent eyespots are a dominant feature of objects for human perceptual responses. We examined whether young children perceive eyespots as a dominant object feature. One hundred and nineteen children from the first, second, and third grades were presented with small manikins, called “Joopes” that varied in the number, type, and arrangement of facial features. Four kinds of Joope heads were used: single element (eyes, mouth, or beak only), monovalent (spatially concordant eyes and mouth, or eyes and beak), ambivalent (asymmetrical eyes and beak, or eyes and mouth), and cyclopean (single eye with orthogonal beak). Two task groups (Peepers and Gobs) ‘helped’ the Joopes to either ‘see’ their food or ‘eat’ it, by placing food in one of 24 feeding dishes. Results indicated that responses made to the ambivalent Joopes differed, with greater ‘drift’ shown by the ‘eating’ group towards the ‘seeing’ responses than by the ‘seeing’ group towards the ‘eating’ responses. The dominant role of eyespots was thus confirmed for children in the second and third grades, but response inconsistencies in the youngest group suggested difficulties in handling incongruent stimuli. The implications of these results for understanding basic perceptual processes are discussed.
Is the Acquisition of Basic-Colour Terms in Young Children Constrained?
Authors: Pitchford Nicola J , Mullen Kathy T
Published: November 2002

We investigated whether the learning of colour terms in childhood is constrained by a developmental order of acquisition as predicted by Berlin and Kay [1969 Basic Color Terms (Berkeley, CA: University of California Press)]. Forty-three children, aged between 2 and 5 years and grouped according to language ability, were given two tasks testing colour conceptualisation. Colour comprehension was assessed in a spoken-word-to-colour-matching task in which a target colour was presented in conjunction with two distractor colours. Colour naming was measured in an explicit naming task in which colours were presented individually for oral naming. Results showed that children's knowledge of basic-colour terms varied across tasks and language age, providing little support for a systematic developmental order. In addition, we found only limited support for an advantage for the conceptualisation of primary (red, green, blue, yellow, black, white) compared to non-primary colour terms across tasks and language age. Instead, our data suggest that children acquire reliable knowledge of nine basic colours within a 3-month period (35.6 to 39.5 months) after which there is a considerable lag of up to 9 months before accurate knowledge of the final two colours (brown and grey) is acquired. We propose that children acquire colour term knowledge in two distinct time frames that reflect the establishment of, first, the exterior (yellow, blue, black, green, white, pink, orange, red, and purple) and, second, the interior structure (brown and grey) of conceptual colour space. These results fail to provide significant support for the order predicted by Berlin and Kay, and suggest, instead, that the development of colour term knowledge is largely unconstrained.
How do the Internal Details of the Object Contribute to Recognition?
Authors: Mitsumatsu Hidemichi , Yokosawa Kazuhiko
Published: November 2002

Object recognition becomes difficult when the main axis of the object is foreshortened. It has previously been reported that this so-called foreshortened disadvantage is larger when the silhouette of the object is presented than when the line drawing of the object is presented. The pronounced foreshortened disadvantage in silhouette recognition indicates that the internal details of the object, which are absent in the silhouette, provide useful information, particularly when the main axis is foreshortened. But the role of these internal details remains controversial. One account for the pronounced disadvantage is that the internal details contribute to the derivation of the main axis. The other account is that internal details provide the distinctive features that are directly matched to the object represented in memory. The aim in the present study was to determine which of these two explanations best accounts for the differential foreshortened disadvantage between line drawings and silhouettes. To reduce the uncertainty regarding the axis orientation, a 3-D arrow indicating the orientation of the main axis was presented as a cue before the object itself was presented. As a result, the difference in the foreshortened disadvantage between silhouettes and line drawings disappeared. This indicated that the pronounced foreshortened disadvantage for silhouettes was caused by a lack of axis information. In other words, the internal details provided the information necessary for axis derivation when the axis was foreshortened.
The Color of Two Alphabets for a Multilingual Synesthete
Authors: Mills Carol Bergfeld , Viguers Meredith L , Edelson Shari K , Thomas Amanda T , Simon-Dack Stephanie L , Innis Joanne A
Published: November 2002

Interviews with a multilingual synesthete (MLS), who experiences colored letters for Roman and Cyrillic alphabets and for digits, revealed stable synesthetic experiences over 2½ – 5 years. Colors of Cyrillic letters were based on Roman letters. Four Stroop tests involving both types of letters showed that MLS was able to name print color faster if the colors matched her synesthetic colors, showing that synesthesia is automatic. Letter-naming times for blocks of color were slower than those of actual letters, supporting unidirectionality of synesthesia. Stroop tests with Roman, but not Cyrillic, letters showed MLS acquired new temporary letter–color pairings and her color-naming times for these were not different from those for her original synesthetic colors.
Feature Integration across Parts in Visual Search
Authors: Xu Yaoda
Published: November 2002

In the present study, participants searched for a conjunction of color and orientation either from the same part of an object (same-part display), or from different parts of an object (different-part display). While no difference was found between the two display conditions in single feature searches, conjunction search in the same-part display was significantly faster than that in the different-part display. This same-part advantage applies to both the inner part as well as the outer part of an object. These results suggest that features are more readily integrated if they are from the same part of an object than if they are from different parts of an object. The formation of object part representations thus influences how features are integrated and encoded during visual information processing.
Vertical Disparity Can Alter Perceived Direction
Authors: Berends Ellen M , van Ee Raymond , Erkelens Casper J
Published: November 2002

It has been well established that vertical disparity is involved in perception of the three-dimensional layout of a visual scene. The goal of this paper was to examine whether vertical disparities can alter perceived direction. We dissociated the common relationship between vertical disparity and the stimulus direction by applying a vertical magnification to the image presented to one eye. We used a staircase paradigm to measure whether perceived straight-ahead depended on the amount of vertical magnification in the stimulus. Subjects judged whether a test dot was flashed to either the left or the right side of straight-ahead. We found that perceived straight-ahead did indeed depend on the amount of vertical magnification but only after subjects adapted (for 5 min) to vertical scale (and only in five out of nine subjects). We argue that vertical disparity is a factor in the calibration of the relationship between eye-position signals and perceived direction.
Effects of Occlusion on Pigeons' Visual Object Recognition
Authors: DiPietro Norma T , Wasserman Edward A , Young Michael E
Published: November 2002

Casual observation suggests that pigeons and other animals can recognize occluded objects; yet laboratory research has thus far failed to show that pigeons can do so. In a series of experiments, we investigated pigeons' ability to ‘name’ shaded, textured stimuli by associating each with a different response. After first learning to recognize four unoccluded objects, pigeons had to recognize the objects when they were partially occluded by another surface or when they were placed on top of another surface; in each case, recognition was weak. Following training with the unoccluded stimuli and with the stimuli placed on top of the occluder, pigeons' recognition of occluded objects dramatically improved. Pigeons' improved recognition of occluded objects was not limited to the trained objects but transferred to novel objects as well. Evidently, the recognition of occluded objects requires pigeons to learn to discriminate the object from the occluder; once this discrimination is mastered, occluded objects can be better recognized.
The Myxoma Poxvirus Protein, M11L, Prevents Apoptosis by Direct Interaction with the Mitochondrial Permeability Transition Pore
Authors: Everett Helen , Barry Michele , Sun Xuejun , Lee Siow Fong , Frantz Christine , Berthiaume Luc G. , McFadden Grant , Bleackley R. Chris
Published: November 2002

M11L, an antiapoptotic protein essential for the virulence of the myxoma poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial membrane potential that accompanies cell death. In this study we show, using a cross-linking approach, that M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) component of the permeability transition (PT) pore. Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L prevents the release of mitochondrial cytochrome c induced by staurosporine or protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also prevents mitochondrial membrane potential loss induced by PPIX, or induced by staurosporine in combination with PK11195, another ligand of the PBR. Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR. We conclude that M11L regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR.
Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non–Self-Ligand
Authors: Munder Markus , Bettelli Estelle , Monney Laurent , Slavik Jacqueline M. , Nicholson Lindsay B. , Kuchroo Vijay K.
Published: November 2002

Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2−/− T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self.
Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes
Authors: Lesage Sylvie , Hartley Suzanne B. , Akkaraju Srinivas , Wilson Judith , Townsend Michelle , Goodnow Christopher C.
Published: November 2002

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet β cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.
Invariant Chain Controls the Activity of Extracellular Cathepsin L
Authors: Fiebiger Edda , Maehr René , Villadangos José , Weber Ekkehard , Erickson Ann , Bikoff Elizabeth , Ploegh Hidde L. , Lennon-Duménil Ana-Maria
Published: November 2002

Secretion of proteases is critical for degradation of the extracellular matrix during an inflammatory response. Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of the p41 splice variant (p4165aa) of major histocompatibility complex class II–associated invariant chain (Ii) binds to the active site of CatL and permits the maintenance of a pool of mature enzyme in endosomal compartments of macro-phages and dendritic cells (DCs). Here we show that interaction of p4165aa with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p4165aa in culture supernatants from antigen-presenting cells (APCs). Extracellular accumulation of mature CatL is up-regulated by inflammatory stimuli as observed in interferon (IFN)-γ–treated macrophages and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the extracellular milieu, released CatL associated with p4165aa is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p4165aa stabilizes CatL in the extracellular environment and induces a local increase in the concentration of matrix-degrading enzymes during inflammation. Through its interaction with CatL, Ii may therefore control the migratory response of APCs and/or the recruitment of effectors of the inflammatory response.
AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency
Authors: Schwieger Maike , Löhler Jürgen , Friel Jutta , Scheller Marina , Horak Ivan , Stocking Carol
Published: November 2002

The translocation (8;21), generating the AML1-ETO fusion protein, is one of the most frequent chromosomal abnormalities associated with acute myelogenous leukemia (AML). To elucidate its role in oncogenesis, bone marrow (BM) cells were infected with a retroviral vector carrying AML1-ETO and transplanted into mice. In contrast to previous transgenic mouse models, we show that AML1-ETO directly stimulates granulopoiesis, suppresses erythropoiesis, and impairs the maturation of myeloid, B, and T lymphoid cells in vivo. To determine the significance of earlier findings that expression of the tumor suppressor ICSBP is often downregulated in AML myeloblasts, AML1-ETO was introduced into BM cells derived from mice lacking the interferon regulatory factor ICSBP. Our findings demonstrate that AML1-ETO synergizes with an ICSBP deficiency to induce myeloblastic transformation in the BM, reminiscent of AML.
Quantitative and Qualitative Changes in V-J α Rearrangements During Mouse Thymocytes Differentiation
Authors: Pasqual Nicolas , Gallagher Maighréad , Aude-Garcia Catherine , Loiodice Mélanie , Thuderoz Florence , Demongeot Jacques , Ceredig Rod , Marche Patrice Noël , Jouvin-Marche Evelyne
Published: November 2002

Knowledge of the complete nucleotide sequence of the mouse TCRAD locus allows an accurate determination V-J rearrangement status. Using multiplex genomic PCR assays and real time PCR analysis, we report a comprehensive and systematic analysis of the V-J recombination of TCR α chain in normal mouse thymocytes during development. These respective qualitative and quantitative approaches give rise to four major points describing the control of gene rearrangements. (a) The V-J recombination pattern is not random during ontogeny and generates a limited TCR α repertoire; (b) V-J rearrangement control is intrinsic to the thymus; (c) each V gene rearranges to a set of contiguous J segments with a gaussian-like frequency; (d) there are more rearrangements involving V genes at the 3′ side than 5′ end of V region. Taken together, this reflects a preferential association of V and J gene segments according to their respective positions in the locus, indicating that accessibility of both V and J regions is coordinately regulated, but in different ways. These results provide a new insight into TCR α repertoire size and suggest a scenario for V usage during differentiation.
Human Autoimmune Sera as Molecular Probes for the Identification of an Autoantigen Kinase Signaling Pathway
Authors: Kamachi Makoto , Le Truc M. , Kim Susan J. , Geiger Meghan E. , Anderson Paul , Utz Paul J.
Published: November 2002

Using human autoimmune sera as molecular probes, we previously described the association of phosphorylated serine/arginine splicing factors (SR splicing factors) with the U1-small nuclear ribonucleoprotein (U1-snRNP) and U3-small nucleolar RNP (snoRNP) in apoptotic cells. SR proteins are highly conserved autoantigens whose activity is tightly regulated by reversible phosphorylation of serine residues by at least eight different SR protein kinase kinases (SRPKs), including SRPK1, SRPK2, and the scleroderma autoantigen topoisomerase I. In this report, we demonstrate that only one of the known SRPKs, SRPK1, is associated with the U1-snRNP autoantigen complex in healthy and apoptotic cells. SRPK1 is activated early during apoptosis, followed by caspase-mediated proteolytic inactivation at later time points. SRPKs are cleaved in vivo after multiple apoptotic stimuli, and cleavage can be inhibited by overexpression of bcl-2 and bcl-xL, and by exposure to soluble peptide caspase inhibitors. Incubation of recombinant caspases with in vitro–translated SRPKs demonstrates that SRPK1 and SRPK2 are in vitro substrates for caspases-8 and -9, respectively. In contrast, topoisomerase I is cleaved by downstream caspases (-3 and -6). Since each of these SRPKs sits at a distinct checkpoint in the caspase cascade, SRPKs may serve an important role in signaling pathways governing apoptosis, alternative mRNA splicing, SR protein trafficking, RNA stability, and possibly the generation of autoantibodies directed against splicing factors.
Parasite-induced Lipoxin A4 Is an Endogenous Regulator of IL-12 Production and Immunopathology in Toxoplasma gondii Infection
Authors: Aliberti Julio , Serhan Charles , Sher Alan
Published: November 2002

The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-γ–dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently, we demonstrated that lipoxin (LX)A4, an eicosanoid mediator that depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on dendritic cell IL-12 production triggered artificially by a T. gondii extract. We now formally establish the physiological relevance of this pathway in the systemic control of IL-12 production induced by live T. gondii infection and demonstrate its function to be distinct from that of IL-10. Thus, T. gondii–exposed wild-type, but not 5-LO–deficient animals, produced high levels of serum LXA4 beginning at the onset of chronic infection. Moreover, 5-LO−/−, in contrast to wild-type mice, succumbed during the same period displaying a marked encephalitis. The increased mortality of the 5-LO−/− animals was also associated with significant elevations of IL-12 and IFN-γ and was completely prevented by the administration of a stable LXA4 analogue. Together, these findings demonstrate a new pathway involving the induction of host LXs for the in vivo regulation of proinflammatory responses during microbial infection.
Genome Dynamics in Aging Mice
Authors: Dollé Martijn E.T. , Vijg Jan
Published: November 2002

Random spontaneous genome rearrangements are difficult to detect in vivo, especially in postmitotic tissues. Using alacZ-plasmid reporter mouse model, we have previously presented evidence for the accumulation of large genome rearrangements in various tissues, including postmitotic tissues, during aging. These rearrangements, which were found to be organ-specific and to increase with age, have one breakpoint in the lacZ-reporter locus and the second elsewhere in the mouse genome. In this present work, we have used a mouse genome sequence database to physically characterize a total of 49 genome rearrangements in the brain, heart, and liver from young and old mice at two lacZ-plasmid reporter loci. Half of all breakpoints in the mouse genome occurred in chromosomes 3 and 4, each carrying a lacZ-reporter cluster, at distances varying from <100 kb to 66 Mb, indicating intrachromosomal deletions or inversions. The other half of the breakpoints in the mouse genome was found randomly on any of the other chromosomes, indicating translocations. Alternatively, part of the intra- and extrachromosomal events could involve transpositions. Regions of extended homology were not found at the breakpoints. These results lead us to postulate potential mechanisms for the origin of large genome rearrangements in mouse tissues and to predict their possible impact as a potential cause of aging.
Novel PAX6 Binding Sites in the Human Genome and the Role of Repetitive Elements in the Evolution of Gene Regulation
Authors: Zhou Yi-Hong , Zheng Jessica B. , Gu Xun , Saunders Grady F. , Yung W.-K. Alfred
Published: November 2002

Pax6 is a critical transcription factor in the development of the eye, pancreas, and central nervous system. It is composed of two DNA-binding domains, the paired domain (PD), which has two helix–turn–helix (HTH) motifs, and the homeodomain (HD), made up from another HTH motif. Each HTH motif can bind to DNA separately or in combination with the others. We identified three novel binding sites that are specific for the PD and HD domains of human PAX6 from single-copy human genomic DNA libraries using cyclic amplification of protein binding sequences (CAPBS) and electrophoretic mobility shift assays (EMSAs). One of the binding sites was found within sequences of repetitive Alu elements. However, most of the Alu sequences were unable to bind to PAX6 because of a small number of mismatches (mostly in CpG dinucleotide hot spots) in the consensus Alu sequences. PAX6 binding Alu elements are found primarily in old and intermediate-aged Alu subfamilies. These data along with our previously identified B1-type Pax6 binding site showed that evolutionarily conserved Pax6 has target sites that are disparate in primates and rodents. This difference indicates that human and mouse Pax6-regulated gene networks may have evolved through these lineage-specific repeat elements.

[The sequence data from this study have been submitted to GenBank under accession no. AF451322. The following individual kindly provided reagents, samples, or unpublished information as indicated in this paper: L. Yu.]
SNPSTRs: Empirically Derived, Rapidly Typed, Autosomal Haplotypes for Inference of Population History and Mutational Processes
Authors: Mountain Joanna L. , Knight Alec , Jobin Matthew , Gignoux Christopher , Miller Adam , Lin Alice A. , Underhill Peter A.
Published: November 2002

Each independently evolving segment of the genomes of a sexually reproducing organism has a separate history reflecting part of the evolutionary history of that organism. Uniparentally or clonally inherited DNA segments such as the mitochondrial and chloroplast genomes and the nonrecombining portion of the Y chromosome have provided, to date, most of the known data regarding compound haplotypic variation within and among populations. These comparatively small segments include numerous polymorphic sites and undergo little or no recombination. Recombining autosomes, however, comprise the major repository of genetic variation. Technical challenges and recombination have limited large-scale application of autosomal haplotypes. We have overcome this barrier through development of a general approach to the assessment of short autosomal DNA segments. Each such segment includes one or more single nucleotide polymorphisms (SNPs) and exactly one short tandem repeat (STR) locus. With dramatically different mutation rates, these two types of genetic markers provide complementary evolutionary information. We call the combination of a SNP and a STR polymorphism a SNPSTR, and have developed a simple, rapid method for empirically determining gametic phase for double and triple heterozygotes. Here, we illustrate the approach with two SNPSTR systems. Although even one system provides insight into population history, the power of the approach lies in combining results from multiple SNPSTR systems.

[Supplemental material is available online at http://www.genome.org. The following individual kindly provided reagents, samples, or unpublished information as indicated in this paper: L. Luca Cavelli-Sforza.]