bluuebunny/crossref_metadata_2025 huggingface dataset:
A Three-Dimensional, Adaptive, Godunov-Type Model for Global Atmospheric Flows
Authors: Hubbard M. E. , Nikiforakis N.
Published: July 2003

In this paper a Godunov-type methodology is applied to three-dimensional global atmospheric modeling. Numerical issues are addressed regarding the formulation of the tracer advection problem, the application of dimensional splitting, and the implementation of a Godunov-type scheme, based on the WAF approach, on spherical geometries. Particular attention is paid to addressing the problems that arise because of the convergence of the grid lines toward the Poles. A three-dimensional model is then built on the sphere that is based on a uniform longitude–latitude–height grid. This provides the framework within which an adaptive mesh refinement (AMR) algorithm is applied, to enhance the efficiency and accuracy with which results are obtained. These methods are not commonly used in the area of atmospheric modeling, but AMR in particular is commonly used with great success in other areas of computational fluid dynamics. The model is initially validated using a series of idealized case studies that have exact solutions, but is then developed into an offline model of tracer advection, forced by data from meteorological analyses, suitable to study the evolution of trace chemical species in the atmosphere.
Use and Impact of Automated Aircraft Data in a Global 4DVAR Data Assimilation System
Authors: Cardinali Carla , Isaksen Lars , Andersson Erik
Published: July 2003

The use of automated aircraft data [Aircraft Meteorological Data Relay (AMDAR) and Aircraft Communication Addressing and Reporting System (ACARS)] has recently been extended in ECMWF's operational 4DVAR data assimilation system. Herein, a modified data selection procedure is reported on that allows the use of more aircraft profiling data during the aircraft's ascending and descending phase, and more of the most frequent reports at cruise level. It is shown that the accuracy of analyzed jet streams is improved through these changes, as verified against independent (non–real time) aircraft data that had not been used in the experiments. The modifications are shown to have a clear positive impact on the short- and medium-range forecast performance. The revised aircraft usage was implemented operationally in January 2002.

The impact in 4DVAR of profiles from American and European automated aircraft in ascending and descending phase has been tested in a data denial impact study, for January and July 2001. This particular impact study was run partly on the request of the WMO/Commission for Basic Systems (CBS) Expert Team on data requirements and the redesign of the global observing system. Their interest is in testing whether a modern data assimilation system (such as 4DVAR) obtains substantial benefit from the aircraft profiles, which sample very irregularly in space and time, given that America and Europe are relatively well covered by radiosondes and wind profilers. The results show a substantial positive impact of the profiling aircraft data on analysis and forecast accuracy. The short-range forecast performance is improved over North America, the North Atlantic, and Europe. In the medium range a clear positive impact is found in the North Atlantic, the European, and Arctic areas in the winter period, and beyond day 6 in the summer period. These results are statistically significant and support the ongoing WMO initiative for further expansion of the AMDAR/ACARS coverage. The results also illustrate the effectiveness of 4DVAR with respect to observations that are irregularly distributed in space and time.
Local and Regional Discriminators of Mesoscale Convective Vortex Development in Arizona
Authors: Brommer David M. , Balling Robert C. , Cerveny Randall S.
Published: July 2003

In approximately half of Arizona's summer season (June–September) mesoscale convective systems evolve into mesoscale convective vortices (MCVs). Analysis of satellite imagery identified MCVs in Arizona over the period 1991–2000, and local and regional rawinsonde data discriminated conditions conducive for MCV development. These results indicate that MCVs are more likely to form from convective systems when the local and regional environments are characterized by relative stability in the 850–700-hPa layer and moderate wind shear in the 500–200-hPa layer. These characteristics are similar to results reported for MCV development in the central United States.
Real-Time Multimodel Superensemble Forecasts of Atlantic Tropical Systems of 1999
Authors: Eric Williford C. , Krishnamurti T. N. , Torres Ricardo Correa , Cocke Steven , Christidis Zaphiris , Vijaya Kumar T. S.
Published: July 2003

In this paper, Atlantic hurricane forecasts for the year 1999 are addressed. The methodology for these forecasts is called the multimodel superensemble. This statistical method makes use of the real-time forecasts provided by a number of operational and research models to construct the superensemble forecasts. This method divides the forecast time line into two phases: a training phase and a forecast combining phase. The training phase includes an inventory of past applicable hurricane forecasts, each by the multimodels. The model biases of position and intensity errors of past forecasts are summarized via a simple linear multiple regression of these forecasts against the best-observed estimates of position and intensity. These statistics are next passed on to future forecasts of the multimodels in order to forecast the hurricanes of 1999. This method was first tested for the hurricanes of 1998 with considerable success, with some of those results summarized here. Those statistics were refined for the 1999 Atlantic hurricane season. Overall, the main result of the seasonal summary is that the position and intensity errors for the multimodel superensemble are generally less than those of all of the participating models during 1–5-day real-time forecasts. Some of the major storms of the 1999 season, such as Dennis, Floyd, Irene, and Lenny, were extremely well handled by this superensemble approach. The message of this study is that the proposed approach may be a viable way to construct improved real-time forecasts of hurricane positions and intensity.
A Numerical Study of Early Summer Regional Climate and Weather over LSA-East. Part I: Model Implementation and Verification
Authors: Zhang Da-Lin , Zheng Wei-Zhong , Xue Yong-Kang
Published: July 2003

The Pennsylvania State University–NCAR Mesoscale Model (MM5) and a simplified simple biosphere (SSiB) scheme are modified and then coupled to study various regional climate and weather problems. These modifications include correcting the moisture and cloud hydrometeor fields to ensure the mass conservation; incorporating the effects of dissipative heating to ensure total energy conservation; decoupling soil and vegetation types in specifying various surface parameters; and eliminating the shortwave radiation reaching the surface at points where deep convection occurs.

A 30-day integration of June 1998 over the Midwest states was used to examine the model's capability in capturing the observed wet regional climate and the passage of several mesoscale weather events. It is found that the coupled model reproduces the distribution and magnitude of monthly accumulated precipitation, the time series of area-integrated precipitation, surface pressures, and diurnal changes in surface temperatures, low-level winds and precipitation, as well as the evolution of precipitation systems across the central United States. In particular, the model reproduces well many daily weather events, including the distribution and intensity of low-level temperature and pressure perturbations and precipitation, even up to a month. The results suggest that the daily temperature, clouds, and precipitation events from the weekly to monthly scales, as well as their associated regional climate phenomena, could be reasonably simulated if the surface, boundary layer, radiation, and convective processes are realistically parameterized, and the large-scale forcing could be reasonably provided by general circulation models.
The Influence of the Downstream State on Extratropical Transition: Hurricane Earl (1998) Case Study
Authors: McTaggart-Cowan R. , Gyakum J. R. , Yau M. K.
Published: July 2003

The multitude of tropical–extratropical interactions that occur during an extratropical transition (ET) complicate the prediction and diagnosis of these extreme events. This study focuses on the analysis of a double ET and reintensification event that took place between 5 and 7 September 1998. Ex-Hurricanes Earl and Danielle reintensified rapidly over the western and eastern North Atlantic, respectively. A set of simulations designed to test the sensitivity of Earl's ET to features in the downstream state was run using a set of idealizations for a numerical model's initial and boundary conditions downstream of ex-Hurricane Earl. Dynamic tropopause analyses and the “PV thinking” paradigm applied under the Eady model highlight important developmental and structural differences between the tests.

In fact, two distinct solution modes are diagnosed both in the control and in the sensitivity tests. Earl's ET proceeds according to a “baroclinic mode” of redevelopment, whereas Danielle displays distinct “tropical mode” ET signatures throughout the period of investigation. The presence of a strong zonal jet immediately downstream of the transitioning cyclone is found to be sufficient to induce a baroclinic mode of redevelopment characterized by cyclonic potential vorticity rollup and strong near-surface frontogenesis. Under the influence of an upstream jet in isolation, the reintensification takes on distinctly tropical characteristics as the enhanced northward intrusion of warm, moist air ahead of the system creates a local environment favorable for a tropical mode of redevelopment. A description of the dynamics associated with these two distinct redevelopment modes may aid in the understanding and prediction of these events.
Adolescent Suicide From an International Perspective
Authors: Lester David
Published: July 2003

A review of international suicide rates indicates that although youth suicide rates are high, they are lower than rates for the elderly, have increased less dramatically in recent decades, and are higher for boys than for girls. It is argued that the increases in adolescent suicide rates that have occurred in some nations are a result of improved quality of life for adolescents, a factor that leads young people to blame themselves for failure.
Introduction: The Elusive Idea of Utopia
Authors: Levitas Ruth
Published: July 2003

This introductory article discusses the contributions to this number in the light of some general issues arising out of recent writing on utopia. It notes the wide variety of views on the question of definition of utopia, ranging from the anti-utopian dismissal of it as totalitarianism to a broad and flexible vehicle of desire. It traces the shifting accents of utopia consequent on the move beyond modernity - a shift from time to space and from content to process. Only a flexible approach reflected in the variety of articles in this collection can offer glimpses of the most elusive utopia, the transcendence of loss and longing.
Utopia with no Topos
Authors: Bauman Zygmunt
Published: July 2003

To measure the life `as it is' by a life `as it might or should be' is a defining, constitutive feature of humanity. The urge to transcend is nearest to a universal, and arguably the least destructible, attribute of human existence. This cannot be said, however, of its articulations into `projects' - that is, of cohesive and comprehensive programmes of change and of visions of life that the change is hoped to bring about - visions that stand out of reality, adumbrating a fully and truly different, alternative world. For the constantly present transgressive urge to be articulated into such projects, some less common conditions must arise. Utopia is one of the forms such uncommon articulations may take. This article explores the conditions that defined that form - those of modernity in its initial `solid' stage, a form that was marked and set apart from other articulations of the transgression urge by two remarkable attributes: territoriality and finality. It is concluded that in the transgressive imagination of `liquid modernity' the `place' (whether physical or social) has been replaced by the unending sequence of new beginnings, inconsequentiality of deeds has been substituted for fixity of order, and the desire for a different today has elbowed out concern with a better tomorrow.
Mannheim's Utopia Today
Authors: Turner Charles
Published: July 2003

This article argues that Mannheim's work contains three distinct accounts of utopia. Two of these - utopia in its classical meaning as opposition to the given and utopia in its association with democratic planning - are well known. The third is found in Mannheim's reflections on the problem of ecstasy. In suggesting a utopia of individualist self-defnition and `pure relationship' it anticipates the recent writings of Beck, Bauman and Giddens.
Political Theory as Utopia
Authors: Lassman Peter
Published: July 2003

Political theory has been described as an `enterprise of discovery' that carries within it the danger of utopianism. This article explores one aspect of that danger: the question of the paradoxical or circular nature of much political thinking. This seems to be both a necessary and an impossible feature of such theorizing. Political theory itself seems to require an idea of utopia that is, by definition, impossible to achieve.
Aspects of the Western Utopian Tradition
Authors: Kumar Krishan
Published: July 2003

The western utopia has both classical and Judaeo-Christian roots. From the Greeks came the form of the ideal city, based on reason, from Jews and Christians the idea of deliverance through a messiah and the culmination of history in the millennium. The Greek conception placed utopia in an ideal space, the Christian conception in an ideal time. The modern utopia, dating from Thomas More's Utopia (1516), drew upon both these traditions but added something distinctive of its own. Following More, the modern utopia has developed as a literary form whose closest relative is the novel. This, I argue, is its great strength. Unlike the abstract utopias of social and political philosophy, such as Marxism or anarchism, the `concrete utopia' of writers such as Edward Bellamy, William Morris and H. G. Wells paints `pleasing pictures of daily life' which both impel us to desire the good society and give us the tools by which to assess it. It is in this respect that utopia - and its mirror-image, the anti-utopia - developed as a distinct literary genre, separating it from other forms of picturing the ideal society in both east and west.
Utopia@Second_Millennium. Daedalus_Meets_Job
Authors: Myerson George
Published: July 2003

Through dialogue new worlds can be imagined. In this imaginary dialogue between the vision of Daedalus, speaking through J. B. S. Haldane, and the Old Testament visionary, Job, the relationship between nature and science is re-explored, re-examined and re-engaged. Their words bounce back off the media's contemporary imagining of the BSE crisis in Britain, an episode that profoundly questioned this nature-science interrelationship.
Italian Fascism and Utopia
Authors: Burdett Charles
Published: July 2003

Considering a number of recent works on the ideology and culture of Fascism, the article explores how the concept of utopia, as formulated by different thinkers, can prove useful in attempting to unlock some of the mechanisms through which Fascism sought to manipulate the imagination and the aspirations of Italians. It focuses on the written accounts of writers and journalists who reported on the supposed achievements of the regime both in Italy and in the newly established colonies. It examines the cult of Rome, which was increasingly to become the symbolic language of Fascism, and explores how, in the writings of one journalist after another, the regime was represented as having recovered the powerful utopia of the ancient past. The article then looks at the kind of rhetoric that surrounded some of the most important building projects that took place in Italy in the 1930s. It suggests that the creation of a blueprint for an ideal society was central to this rhetoric and that the notion of the arrival in an earthly paradise was to form the master narrative for most representations of Mussolini's newly acquired African territories. The article then looks at some of the competing versions of utopia that were presented, albeit subliminally, in the official media of the time. It examines some of the dystopian images of the United States that were manufactured on the eve of the Second World War. It concludes by pointing to the violence and intolerance imbedded within the utopian project of Italian Fascism.
Arcadia as Utopia in Contemporary Landscape Design: The Work of Bernard Lassus
Authors: Bann Stephen
Published: July 2003

This article considers the concept of the utopia from the point of view of garden design. It begins with an evocation of the `Jardin de Julie', the literary garden described in Rousseau and acutely analysed by Louis Marin. It then passes to a series of actual gardens created by the French contemporary designer Bernard Lassus, in which the use of landscape effects is seen as achieving similar dislocations of space and incitements to the imagination.
Utopia, Counter-Utopia
Authors: Osborne Thomas
Published: July 2003

This article addresses the question of utopia through some reflections on the work of the Russian writer Andrei Platonov (1899-1951). Platonov's work represents an inspirational series of investigations into the circumstances of utopia: not so much utopia as fantasy, nor utopia as actualized in failure, nor even dystopia, but what is here termed `actually existing utopia'. As such his work captures aspects of utopianism that may have been largely opaque to the investigations of either literary versions of the utopian imagination or utopian versions of social science. Platonov shows us an `anthropological' dimension inherent within the utopian impulse: that we are, so to speak, `utopological' beings. And to this dimension of ourselves he applies a critical style that is not straightforwardly anti-utopian or dystopian but what is called here `counter-utopian'.
Organization as Reply: Henri Bergson and Casual Organization Theory
Authors: Linstead Stephen
Published: July 2003

This paper introduces a symposium of three other papers on the work of Henri Bergson, which develop his idea of creative evolution and argue for the continuing relevance and vitality of Bergson's work for contemporary organization studies. Bergson's corpus is reviewed, along with some suggestions as to his relevance for contemporary organization theory. It is argued that Bergson's work would view organization as part of its object, a process that is changed by that engagement in non-dialectical conversation with it. Organizing, then, is a reply to the object, an act that creates its own possibility. Calculative and formalistic organization theory fails to take into account the importance of intuition as a form of knowing, responsive to the shifting nature of both its object and itself over time, which a casual organization theory, on Bergsonian lines, would do. However, there is no Bergsonian system or programme to be offered here-merely an introduction to some of the rich veins of ideas in his work, and an invitation to engage with them-an invitation, which, like all invitations, invites reply.
The (R)Evolution of New Product Innovation
Authors: O'Shea Anthony
Published: July 2003

In this paper, I argue that the management and engineering literatures on new product innovation conceive it as evolving by some form of biological evolutionary mechanism: punctuated equilibrium, neo-Lamarckian genetic transfer or neo-Darwinian natural selection. These accounts hold out the possibility of `best practice' models based on particular views of time and progress that are too limiting to adequately explain radical innovation in terms of a process rather than the `final' product. I then turn to the works of Henri Bergson to consider how these may help us to consider the processual quality of innovation.
Organizational Development and the Ontology of Creative Dialectical Evolution
Authors: Calori Roland
Published: July 2003

This paper invites organizational theorists to a double stretching, towards philosophy on the one hand and towards practitioners' lay theories on the other. We rely on Henri Bergson's ontology of creative evolution so as to build a `quad-motor' theory explaining the process of development in organizations and to formulate propositions on the relationships between organizational development and the lay ontology of organizational members. Then we illustrate the links between philosophy and practice, and show how the analysis of a narrative by a practitioner (Michel Barthod, Chief Executive of Salomon, a high-growth company, in the 1980s) can elicit his lay ontology, thus making possible future empirical corroborations of the above propositions. This narrative is in line with Bergson's ontology of creative (dialectical) evolution, and also contains the concepts of an integrative framework explaining organizational development. In the third section, inspired by the philosopher, Henri Bergson, and by the practitioner, Michel Barthod, we build such a framework in which becoming and relating are two central intertwined concepts.
Mind the Gap? A Processual Reconsideration of Organizational Knowledge
Authors: Wood Martin
Published: July 2003

On Henri Bergson's view, the flux of time is reality itself and the things we study are the things that flow. Unfortunately, popular literatures on organizational knowledge are accustomed to seeing the moving by means of the immobile. They perceive knowledge as an already organized state that can be transferred between spatially distinct points. Drawing on Bergson's theory of continual movement (Duration) and Deleuze's concept of transversal communication, I challenge the ontological concern for knowledge production and use between the discrete parts of an organized system. Instead of seeing knowledge as the integration of derived points or positions, I advocate a threefold method of creative involution in which production and use are considered as a living interpenetration of foldings and movements that connect all `things' at all places and times.
Inhibition of acute lymphoblastic and myeloid leukemias by a novel kinase inhibitor
Authors: Grunberger Thomas , Demin Peter , Rounova Olga , Sharfe Nigel , Cimpean Lorand , Dadi Harjit , Freywald Andrew , Estrov Zeev , Roifman Chaim M.
Published: July 2003

In recent years, synthetic tyrosine kinase inhibitors have made a rapid transition from basic research to therapeutic application. These compounds represent a major clinical advance in the approach to cancer in their relative specificity of action and decreased toxicity. We report here the effects of a novel tyrosine kinase inhibitor CR4 that interferes with growth-promoting pathways to markedly inhibit the growth and survival of both Philadelphia-positive and -negative acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). While efficiently ablating leukemic cell growth, normal cell growth and differentiation remain unaffected by CR4. CR4 demonstrates an ability to inhibit the function of multiple growth-critical kinases and yet exhibits a low level of cytotoxicity. These findings suggest that CR4 may prove to be highly effective as a therapeutic agent. (Blood. 2003;102:4153-4158)
Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population
Authors: Kustikova Olga S. , Wahlers Anke , Kühlcke Klaus , Stähle Birgit , Zander Axel R. , Baum Christopher , Fehse Boris
Published: July 2003

Retroviral vectors are commonly used in clinical gene therapy, but recent observations of insertional oncogene activation in preclinical and clinical settings have forced a discussion of their safety. Here we investigated the relationship between retroviral transduction efficiency in mass cultures and the actual number of integrated vector copies in single cells using K562 leukemia and primary CD34+ cells. We found an exponential increase of integration numbers correlated to gene transfer rates and a linear increase of expression levels with insertion frequency. On average we detected one vector insertion per transduced cell for a gene transfer of less than 30%, 3 for 60%, and approximately 9 for 90% (in K562). Clonal analysis revealed strikingly increased variations of both transgene copy numbers (more than 20-fold in primary cells) and expression levels associated with higher transduction. Therefore, limiting retroviral gene transfer to approximately 30% may be suggested to avoid generating clones containing multiple insertions.
A role for Syk-kinase in the control of the binding cycle of the β2 integrins (CD11/CD18) in human polymorphonuclear neutrophils
Authors: Willeke Thomas , Schymeinsky Jürgen , Prange Peggy , Zahler Stefan , Walzog Barbara
Published: July 2003

A fine control of β2 integrin (CD11/CD18)-mediated firm adhesion of human neutrophils to the endothelial cell monolayer is required to allow ordered emigration. To elucidate the molecular mechanisms that control this process, intracellular protein tyrosine signaling subsequent to β2 integrin-mediated ligand binding was studied by immunoprecipitation and Western blotting techniques. The 72-kDa Syk-kinase, which was tyrosine-phosphorylated upon adhesion, was found to coprecipitate with CD18, the β-subunit of the β2 integrins. Moreover, inhibition of Syk-kinase by piceatannol enhanced adhesion and spreading but diminished N-formyl-Met-Leu-Phe-induced chemotactic migration. The enhancement of adhesiveness was associated with integrin clustering, which results in increased integrin avidity. In contrast, piceatannol had no effect on the surface expression or on the affinity of β2 integrins. Altogether, this suggests that Syk-kinase controls alternation of β2 integrin-mediated ligand binding with integrin detachment.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-α promote the NF-κB-dependent maturation of normal and leukemic myeloid cells
Authors: Secchiero Paola , Milani Daniela , Gonelli Arianna , Melloni Elisabetta , Campioni Diana , Gibellini Davide , Capitani Silvano , Zauli Giorgio
Published: July 2003

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-α induced monocytic maturation of primary normal CD34-derived myeloid precursors and of the M2/M3-type acute myeloid leukemia HL-60 cell line, associated to increased nuclear factor (NF)-κB activity and nuclear translocation of p75, p65, and p50 NF-κB family members. Consistently, both cytokines also induced the degradation of the NF-κB inhibitors, IκBα and IκBɛ, and up-regulated the surface expression of TRAIL-R3, a known NF-κB target. However, NF-κB activation and IκB degradation occurred with different time-courses, since TNF-α was more potent, rapid, and transient than TRAIL. Of the two TRAIL receptors constitutively expressed by HL-60 (TRAIL-R1 and TRAIL-R2), only the former was involved in IκB degradation, as demonstrated by using agonistic anti-TRAIL receptor antibodies. Moreover, NF-κB nuclear translocation induced by TRAIL but not by TNF-α was abrogated by z-IETD-fmk, a caspase-8-specific inhibitor. The key role of NF-κB in mediating the biological effects of TNF-α and TRAIL was demonstrated by the ability of unrelated pharmacological inhibitors of the NF-κB pathway (parthenolide and MG-132) to abrogate TNF-α- and TRAIL-induced monocytic maturation. These findings demonstrate that NF-κB is essential for monocytic maturation and is activated via distinct pathways, involving or not involving caspases, by the related cytokines TRAIL and TNF-α.
Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species
Authors: Kusmartsev Sergei , Gabrilovich Dmitry I
Published: July 2003

It is well established that tumor growth is associated with accumulation of immature myeloid cells (ImC). They play an important role in tumor-associated immune suppression. ImC accumulate not only in tumor-bearing hosts but also in immunized, tumor-free hosts or hosts infected with bacterial pathogens. The kinetics of ImC in these mice is different. If in tumor-bearing mice, the number of ImC continues to increase with tumor progression in tumor-free mice after an initial spike, it decreases to the control level. Here, we have investigated the mechanisms of ImC accumulation in tumor-bearing hosts by comparing differentiation of ImC obtained from tumor-free and tumor-bearing mice. In the presence of appropriate growth factors, ImC isolated from tumor-free mice quickly differentiated in vitro into mature dendritic cells (DC), macrophages, and granulocytes. In contrast, differentiation of ImC from tumor-bearing mice was significantly delayed. Similar results were obtained in vivo after adoptive transfer of ImC into naïve, congeneic mice. ImC transferred into tumor-bearing recipients failed to differentiate into DC or macrophages. ImC from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC obtained from tumor-free mice. Hydrogen peroxide (H2O2) but not superoxide radical anions was found to be the major part of this increased ROS production. In vitro experiments demonstrated that scavenging of H2O2 with catalase induced differentiation of ImC from tumor-bearing mice into macrophages. Thus, this is a first demonstration that tumors may prevent differentiation of antigen-presenting cells by increasing the level of endogenous H2O2 in immature myeloid cells.
Dramatic increase of telomerase activity during dendritic cell differentiation and maturation
Authors: Ping Lin , Asai Azusa , Okada Aki , Isobe Kenichi , Nakajima Hideo
Published: July 2003

Telomerase, the reverse transcriptase that maintains telomere DNA, is usually undetectable in most adult tissues but is positive in embryonic tissues and in cancers. In addition, freshly islolated or in vitro-activated lymphocytes were shown to express high levels of telomerase activity, although its expression in myeloid cells including dendritic cells (DCs) is largely unknown. Here, we investigated telomerase activity during the differentiation and maturation process of DCs. In vitro culture of bone marrow (BM) cells with granulocyte macrophage-colony stimulating factor and interleukin-4 induced a dramatic increase of telomerase activity accompanied with their differentiation into DCs. Furthermore, stimulation with microbial components such as lipopolysaccharide (LPS), which triggers maturation of DCs, augmented the activity. In vivo responses of telomerase activity were also observed in splenic DCs by injection of LPS intraperitoneally. It is interesting that in old mice, telomerase activity of splenic DCs was significantly higher than young mice but rather decreased after LPS stimulation. By measuring expression of cell-surface activation markers, splenic DCs of old mice responded poorly to LPS stimulation. Such poor responses to LPS were also observed in BM-derived DCs. These different features of DCs between young and old mice may contribute to a pathogenesis to microbial infections.
TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG
Authors: Heldwein Kurt A , Liang Michael D , Andresen Tonje K , Thomas Karen E , Marty Aileen M , Cuesta Natalia , Vogel Stefanie N , Fenton Matthew J
Published: July 2003

Toll-like receptor (TLR) proteins mediate cellular activation by microbes and microbial products. To delineate the role of TLR proteins in the development of host immune responses against mycobacteria, wild-type and TLR-deficient mice were infected with nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin (BCG). Two weeks after intraperitoneal challenge with BCG, few bacilli were present in the lungs of wild-type and TLR4−/− mice, whereas bacterial loads were tenfold higher in the lungs of infected TLR2−/− mice. BCG challenge in vitro strongly induced proinflammatory cytokine secretion by macrophages from wild-type and TLR4−/− mice but not by TLR2−/− macrophages. In contrast, intracellular uptake, intracellular bacterial growth, and suppression of intracellular bacterial growth in vitro by interferon-γ (IFN-γ) were similar in macrophages from all three mouse strains, suggesting that BCG growth in the lungs of TLR2−/− mice was a consequence of defective adaptive immunity. Antigenic stimulation of splenocytes from infected wild-type and TLR4−/− mice induced T cell proliferation in vitro, whereas T cells from TLR2−/− mice failed to proliferate. Unexpectedly, activated CD4+ T cells from both TLR-deficient mouse strains secreted little IFN-γ in vitro compared with control T cells. A role for TLR4 in the control of bacterial growth and IFN-γ production in vivo was observed only when mice were infected with higher numbers of BCG. Thus, TLR2 and TLR4 appear to regulate distinct aspects of the host immune response against BCG.
Retinal transplantation: progress and problems in clinical application
Authors: Lund R D , Ono S J , Keegan D J , Lawrence J M
Published: July 2003

There is currently no real treatment for blinding disorders that stem from the degeneration of cells in the retina and affect at least 50 million individuals worldwide. The excitement that accompanied the first studies showing the potential of retinal cell transplantation to alleviate the progress of blindness in such diseases as retinitis pigmentosa and age-related macular degeneration has lost some of its momentum, as attempts to apply research to the clinic have failed so far to provide effective treatments. What these studies have shown, however, is not that the approach is flawed but rather that the steps that need to be taken to achieve a viable, clinical treatment are many. This review summarizes the course of retinal transplant studies and points to obstacles that still need to be overcome to improve graft survival and efficacy and to develop a protocol that is effective in a clinical setting. Emphasis is given particularly to the consequences of introducing transplants to sites that have been considered immunologically privileged and to the role of the major histocompatibility complex classes I and II molecules in graft survival and rejection.
Cytokine requirements for the growth and development of mouse NK cells in vitro
Authors: Toomey Jennifer A , Gays Frances , Foster Don , Brooks Colin G
Published: July 2003

Natural killer (NK) cells arise from immature progenitors present in fetal tissues and adult bone marrow, but the factors responsible for driving the proliferation and differentiation of these progenitors are poorly understood. Mouse NK cells had previously been thought not to express interleukin (IL)-2Rα chains, but we show here that immature and mature mouse NK cells express IL-2Rα chain mRNA and that low levels of IL-2Rα chains can be detected on the surface of immature and mature NK cells provided they are cultured in the absence of IL-2. Despite their potential expression of high-affinity IL-2 receptors, immature NK cells only proliferate if IL-2 is present at extremely high concentrations. Surprisingly, IL-15 can also only support the growth of immature NK cells at high, presumably nonphysiological concentrations. Although NK cells express mRNA for the high-affinity IL-15Rα chain, they also express a variety of alternately spliced transcripts whose protein products could potentially disrupt signaling through IL-15 receptors. The requirement for high concentrations of IL-2 and IL-15 suggests that if these cytokines play any role in the proliferative expansion of NK cells in vivo, they act indirectly via other cells or in cooperation with other factors. In support of the latter possibility, we report that the recently described cytokine IL-21 can markedly enhance the proliferation of immature (and mature) NK cells in the presence of doses of IL-2 and IL-15 that by themselves have little growth-promoting activity.
Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-α secretion
Authors: Lahat Nitza , Rahat Michal A , Ballan Mouna , Weiss-Cerem Lea , Engelmayer Miri , Bitterman Haim
Published: July 2003

Monocytes/macrophages in ischemic tissues are involved in inflammation and suppression of adaptive immunity via secretion of proinflammatory cytokines and reduced ability to trigger T cells, respectively. We subjected human mononuclear cells and mouse macrophages to hypoxia and reoxygenation, the main constituents of ischemia and reperfusion, and added lipopolysaccharide (LPS) to simulate bacterial translocation, which frequently accompanies ischemia. We monitored the secretion of tumor necrosis factor α (TNF-α) and the surface expression of human leukocyte antigen-DR and the costimulatory molecules CD80 and CD86 on monocytes/macrophages. Hypoxia selectively reduced the surface expression of CD80 (P<0.01), and synergistically with LPS, it enhanced TNF-α secretion (P<0.003). Reoxygenation reversed both phenomena. In the mouse macrophage cell line RAW 264.7, hypoxia reduced the surface expression of CD80 and increased its concentrations in the supernatants (P<0.01). Down-regulation of the mRNA coding for the membrane-anchored CD80 was observed, suggesting that hypoxia triggers alternative splicing to generate soluble CD80. Cumulatively, these results suggest that hypoxia simultaneously affects monocytes/macrophages to enhance inflammation and reduce their ability to initiate adaptive-immunity responses associated with ischemic injury.
Immunity in the eye: lessons in organ-specific responses
Authors: Ono Santa Jeremy
Published: July 2003

Fifty-five years have past since Sir Peter Medawar first demonstrated that the fate of allografts differs in the skin, brain, subcutaneous tissue, and anterior chamber of the eye. Indeed, these and other experiments performed at the University of Birmingham and University College London not only helped define key paradigms in transplantation biology but introduced the concept of immune privilege in the eye and in other tissues. In the ensuing years, the work from dozens of laboratories has confirmed that immune responses in eye, although sharing many features with immunity in other tissues, are atypical in many respects. This has been hypothesized to stem from the requirement in the eye to hold inflammation in check to preserve visual function. Indeed, inflammatory reactions in different regions of the eye can result in visual impairment and blindness, manifesting in diseases such as vernal keratoconjunctivitis, uveitis, corneal endotheliitis, Mooren’s ulcer, and pemphigoid. The investigation of the cell and molecular basis of the unique nature of immunity in the eye has revealed a remarkably complex network of interactions that controls inflammation while affording immunity. The most recent data generated in this field and the concepts arising from their interpretation were discussed at a symposium held at the University College London in late 2002. Here, we highlight some of the findings discussed at the meeting and introduce in-depth reviews published in this issue of the journal.
Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8
Authors: Biber Knut , Zuurman Mike W , Homan Han , Boddeke Hendrikus W G M
Published: July 2003

It has become clear in the past years that chemokines and chemokine receptors are pivotal regulators of cellular communication and trafficking. In addition to the ∼20 chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are known. We have investigated the orphan mouse chemokine receptor (L-CCR) in HEK 293 cells, a receptor that was originally described in a mouse macrophage cell line. Cells expressing this receptor show pertussis toxin-sensitive chemotaxis and small intracellular calcium transients in response to the chemokines CCL2, CCL7, CCL8, and CCL5. Biotinylated CCL2 binds to L-CCR-expressing cells, and transfection experiments with an L-CCR–green fluorescent protein fusion protein showed L-CCR expression in the membranes of recombinant HEK 293 cells. Although radioligand binding was not detected, it is suggested that L-CCR is a functional chemokine receptor.
Pathways for the regulation of interferon-γ-inducible genes by iron in human monocytic cells
Authors: Oexle Horst , Kaser Arthur , Möst Johannes , Bellmann-Weiler Rosa , Werner Ernst R , Werner-Felmayer Gabriele , Weiss Günter
Published: July 2003

To elucidate iron-regulated interferon-γ (IFN-γ) effector functions, we investigated three IFN-γ-inducible genes [intercellular adhesion molecule-1 (ICAM-1), human leukocyte antigen (HLA)-DR, guanosine 5′-triphosphate-cyclohydrolase I (GTP-CH)] in primary human monocytes and the cell line THP-1. IFN-γ increased the surface expression of ICAM-1 and HLA-DR and stimulated GTP-CH activity. Addition of iron before cytokine stimulation resulted in a dose-dependent reduction of these pathways, and iron restriction by desferrioxamine (DFO) enhanced ICAM-1, HLA-DR, and GTP-CH expression. Iron neither affected IFN-γ binding to its receptor nor IFN-γ receptor surface expression. IFN-γ-inducible mRNA expression of ICAM-1, HLA-DR, and GTP-CH was reduced by iron and increased by DFO by a transcriptional mechanism. Moreover, ICAM-1 and to a lesser extent, GTP-CH and HLA-DR mRNA expression were regulated post-transcriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFN-γ alone. Thus, iron perturbations regulate IFN-γ effector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFN-γ signal-transduction processes.
Control of myeloid activity during retinal inflammation
Authors: Dick Andrew D , Carter Debra , Robertson Morag , Broderick Cathryn , Hughes Edward , Forrester John V , Liversidge Janet
Published: July 2003

Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in “classical” activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.
The immune privilege of corneal grafts
Authors: Niederkorn Jerry Y
Published: July 2003

Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation. In the United States, over 33,000 corneal transplants are performed each year. Unlike other forms of tissue transplantation, keratoplasties are routinely performed without the aid of tissue typing or systemic immunosuppressive drugs. In spite of this, 90% of the first-time corneal transplants will succeed–a condition that demonstrates the immune privilege of keratoplasties. The avascular nature of the corneal allograft bed led many to suspect that corneal grafts were sequestered from the immune apparatus. Although pleasing in its simplicity, this explanation has given way to a more comprehensive hypothesis that embodies multiple, interdependent mechanisms, which promote the long-term survival of corneal allografts. These mechanisms conspire to interrupt the transmission of immunogenic stimuli to peripheral lymphoid tissues; induce the generation of a deviated immune response; and neutralize immune effector elements at the host-graft interface. This paradigm is analogous to a three-legged stool. Disassembly of any one of the three components results in the collapse of immune privilege. Strategies to re-establish corneal immune privilege may have clinical application for high-risk hosts who have rejected previous corneal allografts.
Corneal immunity is mediated by heterogeneous population of antigen-presenting cells
Authors: Hamrah Pedram , Huq Syed O , Liu Ying , Zhang Qiang , Dana M Reza
Published: July 2003

Corneal antigen-presenting cells (APC), including dendritic cells (DC), were thought to reside exclusively in the peripheral cornea. Here, we present recent data from our group demonstrating that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal DC, which function as APC. Although the corneal periphery contains mature and immature resident bone marrow-derived CD11c+ DC, the central cornea is endowed exclusively with immature and precursor DC, both in the epithelium and the stroma, wherein Langerhans cells and monocytic DC reside, respectively. During inflammation, a majority of resident DC undergo maturation by overexpressing major histocompatibility complex class II and B7 (CD80/CD86) costimulatory molecules. In addition to the DC, macrophages are present in the posterior corneal stroma. In transplantation, donor-derived DC are able to migrate to host cervical lymph nodes and activate host T cells via the direct pathway when allografts are placed in inflamed host beds. These data revise the tenet that the cornea is immune-privileged as a result of lack of resident lymphoreticular cells and suggest that the cornea is capable of diverse cellular mechanisms for antigen presentation.