bluuebunny/crossref_metadata_2025 huggingface dataset:
Vox Populi: An Interactive Evolutionary System for Algorithmic Music Composition
Authors: Moroni Artemis , Manzolli Jônatas , Zuben Fernando Von , Gudwin Ricardo
Published: July 2002

While recent techniques of digital sound synthesis have put numerous new sounds on the musician's desktop, several artificial-intelligence (AI) techniques have also been applied to algorithmic composition. This article introduces Vox Populi, a system based on evolutionary computation techniques for composing music in real time. In Vox Populi, a population of chords codified according to MIDI protocol evolves through the application of genetic algorithms to maximize a fitness criterion based on physical factors relevant to music. Graphical controls allow the user to manipulate fitness and sound attributes.
Making Music on the Web
Authors: Duckworth William
Published: July 2002

Cathedral is one of the first extended works of music and art created as a web site. On-line since June 1997, it includes both acoustic and computer music, live webcasts and newly created virtual instruments. The author discusses the conception and development of the site, and outlines future plans for a 48-hour web concert in 2001. Cathedral may be visited at < http://www.monroestreet.com/Cathedral/home.html >.
Tile Automaton: A Model for an Architecture of a Living System
Authors: Yamamoto Tomoyuki , Kaneko Kunihiko
Published: July 2002

To understand an architecture of a living system, “Tile Automaton” is introduced as an abstract model of chemical reaction of molecules scattered over a space. The model consists of tiles of various shapes that stand for molecules. The chemical reaction, induced by the collisions of tiles, is represented by the change of the tile shapes. The rules for reaction are deterministic, and the evolution of the system strongly depends on mutual spatial relationship among tiles. The evolution often leads to self-organization of a “factory,” a set of tiles that produces tiles continuously and keeps its structure. Several interesting phenomena, such as a deformation or a division of a factory, are also observed. It is proposed that the formation of the factory is due to the interference between different aspects of tiles—the shape and the motion. The concept of “entanglement” is introduced as a mechanism of living systems.
An Approach to Biological Computation: Unicellular Core-Memory Creatures Evolved Using Genetic Algorithms
Authors: Suzuki Hideaki
Published: July 2002

A novel machine language genetic programming system that uses one-dimensional core memories is proposed and simulated. The core is compared to a biochemical reaction space, and in imitation of biological molecules, four types of data words (Membrane, Pure data, Operator, and Instruction) are prepared in the core. A program is represented by a sequence of Instructions. During execution of the core, Instructions are transcribed into corresponding Operators, and Operators modify, create, or transfer Pure data. The core is hierarchically partitioned into sections by the Membrane data, and the data transfer between sections by special channel Operators constitutes a tree data-flow structure among sections in the core. In the experiment, genetic algorithms are used to modify program information. A simple machine learning problem is prepared for the environment data set of the creatures (programs), and the fitness value of a creature is calculated from the Pure data excreted by the creature. Breeding of programs that can output the predefined answer is successfully carried out. Several future plans to extend this system are also discussed.
Spatially Explicit Characterization of Acidifying and Eutrophying Air Pollution in Life‐Cycle Assessment
Authors: Huijbregts Mark A. J. , Schöpp Wolfgang , Verkuijlen Evert , Heijungs Reinout , Reijnders Lucas
Published: July 2002

Abstract: Simple models are often used to assess the potential impact of acidifying and eutrophying substances released during the life cycle of products. As fate, background depositions, and ecosystem sensitivity are not included in these models, environmental life‐cycle assessment of products (LCA) may produce incorrect results for these impact categories. This paper outlines the spatially explicit regional air pollution information and simulation model (RAINSLCA), which was developed for the calculation of acidification and terrestrial eutrophication potentials of ammonia (NH3) and nitrogen oxide (NOx) air emissions and acidification potentials for sulfur dioxide (SO2) air emissions for Europe and a number of European regions, taking fate,
The Energetic Metabolism of Societies: Part II: Empirical Examples
Authors: Haberl Helmut
Published: July 2002

Part I of this set of articles proposed methods to account for the energetic metabolism of societies. In this second part, the methods explicated in Part I are used to analyze the energy flows of societies with different “modes of subsistence”: hunter‐gatherers, a contemporary agricultural society in southeastern Asia, and a contemporary industrial society (Austria). The empirical examples are used to demonstrate differences in the “characteristic metabolism” of different modes of sub‐sistence. The energy system of hunter‐gatherers can be described as an “uncontrolled solar energy system,” based mainly upon harvesting biomass without attending to its reproduction. Hunter‐gatherers use only about 0.001% to 0.01% of the net primary production (NPP) of the territory they inhabit. Agricultural societies harness NPP to a much higher extent: Although agriculture often reduces NPP, the amount of biomass that agricultural societies use is much higher (about 20% of potential NPP). Because ecological energy flows are the main source of energy for agricultural societies, NPP strictly limits the energetic metabolism of agricultural societies. Industrial society uses area‐independent energy sources (fossil and nuclear energy), which, however, result in new sustainability problems, such as greenhouse gas emissions. By providing methods to account for changes in energy flows, the metabolism approach proves itself to be a useful concept for analyzing society‐environment interactions. The article demonstrates the difference between the metabolism approach and conventional energy statistics and discusses the significance of the proposed approach for sustainable development.
The Early Post-Stalin Succession Struggle and Upheavals in East-Central Europe: Internal-External Linkages in Soviet Policy Making (Part 3)
Authors: Kramer Mark
Published: July 2002

The East German uprising and the downfall of Lavrentii Beria had profound short- and long-term effects on Soviet policy toward Germany and on the political configuration of the Eastern bloc. This article, the final segment of a three-part analysis of Soviet—East European relations in the early post-Stalin era, discusses the changes in the Soviet bloc at some length. It then ties together the three parts of the analysis by exploring the theoretical implications of the linkages between internal and external events in the Soviet Union and East-Central Europe in 1953, drawing on recent theoretical literature about the connection between domestic and international politics.
A Luce Connection: Senator Keating, William Pawley, and the Cuban Missile Crisis
Authors: Holland Max
Published: July 2002

Documentation from unexpected sources sheds new light on a question that had seemed unresolvable: how Senator Kenneth Keating learned about the emplacement of Soviet missiles in Cuba well before the Kennedy administration did. The new evidence not only reveals the intricacies of this longstanding mystery, but also provides valuable insights about U.S. intelligence operations, the making of U.S. foreign policy, and the rich opportunities for research about the Cold War in the four million pages of documents gathered under the Kennedy Records Collection Act of 1992.
INTERPRETATIVE MODES OF YIN-YANG DYNAMICS AS AN ASIAN HERMENEUTICS
Authors: Kim Hyun Chul Paul
Published: July 2002

This study attempts to explore and exemplify several hermeneutical modes of biblical interpretation in light of Asian philosophical systems, especially the concept of the dynamic relationship between yin and yang . By applying some key aspects of the yin-yang dynamics and by utilizing relevant biblical cases, the writer aims to suggest the productivity of reading the biblical texts in dialogue with Asian stories, traditions, and worldviews. The study delineates four major aspects of the yin-yang concepts: (1) duality and plurality, (2) both-and in contradiction and paradox, (3) reciprocity and change, and (4) harmony and balance. Each aspect is defined from various ancient Chinese philosophical resources. The one prominent feature of yin-yang dynamics is the idea of duality and plurality, in that one source has two aspects and those bipolar entities together construct a multi-dimensional whole. Within this complex structure, the opposite components exist together in a "both-and" mutuality rather than "either-or" reduction. In265.p65 stead of repelling against or reducing to one, the two contradictory ideas are often placed together in a dynamic correlation. This dynamic correlation is not static but fluid, constantly changing and flowing within the mutual reciprocity. Two opposite entities not only stand side-by-side but also coerce, challenge, and correct each other in a constant mutual interaction. This mutual interaction does not occur at a random accident but rather for the dynamic retrieval, retaining, and return to the centrality of balance. After defining each of these aspects, selected biblical exemplifications are discussed, in order to present a case that there are many parallel—both similar and opposite—ideas, traditions, and worldviews between the biblical texts and the yin-yang concepts. The biblical exemplifications mainly focus on Genesis 1 and 2, though cases from some other places are also discussed. Several prospects for the possible potentialities and limitations of utilizing this yin-yang dynamics are suggested at the conclusion.
NEW EVIDENCE RELATING TO THE PROCESS OF ISLAMIZATION IN PALESTINE IN THE EARLY MUSLIM PERIOD THE CASE OF SAMARIA
Authors: Levy-Rubin Milka
Published: July 2002

There is an ongoing discussion among scholars concerning the date and the pace of the process of Islamization in Palestine during the early Muslim period. Evidence concerning this subject is rare. Muslim sources relate that there was a substantial presence of Muslims in the area of Samaria from the tenth century onwards. It has been presumed until now that this was solely a result of immigration of Arab Muslims to this area. Basing itself upon new evidence found in a local Samaritan chronicle, this article strives to show that a small part of this Muslim population originated in Samaritan population which converted to Islam during the early Muslim period mainly as a result of difficult economic conditions. As of now, this is the only evidence we have of mass conversion to Islam in Palestine during the early Muslim period. It should be emphasized that this evidence cannot be applied automatically to the Jewish and Christian communities in Palestine whose circumstances, though similar, were nevertheless somewhat different.
Plutarch's Dualism and the Delphic Cult
Authors: Chlup Radek
Published: July 2002

The article interprets Plutarch's dualism in the light of the Apollo-Dionysus opposition as presented in De E 388e-389c, arguing that Plutarch is no dualist in the strict sense of the word. A comparison of De E 393f-394a with De Iside 369b-d shows that it is only in the sublunary realm of Nature that Plutarch assumes a duality of two distinct Powers; at the higher levels of reality the divine is unified and harmonious. If Plutarch fails to emphasize this point clearly enough, it is because his primary philosophical interests were ethical, not metaphysical.
'SAVED IN THE MAN AND IN THE NATION': THE SACRALIZATION OF THE SOIL IN TWENTIETH-CENTURY IRISH DRAMA
Authors: Richards Shaun
Published: July 2002

Writing in the founding years of the Irish state Daniel Corkery observed that the land was a 'huge force in Irish life' and constituted one of the three elements which made up 'the Irish national being'. But while sacralised in the period of the Literary Revival as the 'hidden spring' from which the Irish nation drew its 'vitality', allegiance to the land has also been seen as a limitation. Working through plays from The Land (1905) to After Easter (1994) this article focuses on the dramatisation of responses to the demand to 'stay on the land and you'll be saved body and soul' as Ireland experiences the physical and psychological deracination consequent upon globalisation.
BEHAVIORAL DIFFERENTIATION OF ADJACENT MARINE AND FLUVIAL POPULATIONS OF THREESPINE STICKLEBACK IN CALIFORNIA: A LABORATORY STUDY
Authors: Peeke Harman , Morgan Lance
Published: July 2002

Threespine sticklebacks (Gasterosteus aculeatus) from marine, estuarine and upstream fresh water were collected from two coastal watersheds in northern California. Laboratory tests of response to behavioral stimuli associated with aggression, courtship and feeding show interpopulation variation. Behavioral responses of populations from the same habitat type were similar, and individuals from up-stream habitats were generally more responsive to stimuli than individuals from the estuarine environments, which in turn were more responsive than marine fish. Different predators and predation pressures are discussed as one possible factor in the evolution of these behavioral variations.
TO SYNCHRONISE OR NOT TO SYNCHRONISE: A DILEMMA FOR YOUNG BIGHORN MALES?
Authors: Ruckstuhl
Published: July 2002

Bighorn sheep (Ovis canadensis) are sexually dimorphic and live in nursery groups, bachelor or mixed groups. To remain in a group, individuals have to synchronise their activity according to the type of group they are in, which may incur a cost for individuals of different body size from the other group members. To test this hypothesis, I calculated the degree of synchrony of activities for each individual within a group. Animals in nursery or bachelor groups were highly synchronised with each other while mixed-age-sex groups had the lowest group synchronisation index. Two and three-year old bighorn males are intermediate in body size between the two adult sexes. Two-year-old males always adjusted their behaviour independent of group type, while three-year-old males synchronised their behaviour when with bachelor, but less so when in nursery groups. I suggest that two- and three-year-old males may face a conflict between synchronising their behaviour to stay in a group and the need to forage according to their own time budgets. I conclude that intermediate-sized young male ungulates of sexually dimorphic species may be better off forming same-sex-age groups.
Food preferences of a fungal-feeding Aphelenchoides species
Authors: Ruess Liliane , Zapata Erick J. Garcia , Dighton John
Published: July 2002

The growth of Aphelenchoides sp. populations was investigated in vitro with
17 different fungal species as food source. Nematode mass cultures were
obtained with saprophytic (Agrocybe, Chaetomium) and especially with
mycorrhizal fungi (Cenococcum, Hymenoscyphus, Laccaria). Mitosporic species,
like Alternaria, Monocillium or Penicillium, were generally meagre or
non-hosts. This poor host suitability is likely due to the release of toxic
metabolites (e.g. antibiotics) and/or to morphological differences (e.g.,
forming of conidiophores) by the fungi. Frequent grazing of nematodes on
mycorrhizal mycelia may be of major significance for the establishment and
maintenance of mycorrhizal associations in the field. Food preference of
Aphelenchoides sp. was tested in choice chamber experiments. Nematodes
showed a marked preference for particular fungal species. They changed food
source with time, indicating a “mixed diet” selection, probably a strategy
to avoid the concentration of toxic metabolites. The attractiveness of a
fungus was not necessarily correlated with its suitability as a host. That a
poor fungal host can be a strong nematode attractant and influence their
spatial distribution in the soil has implications for nematode populations
in the field. In Laborexperimenten wurde die Vermehrung des Nematoden
Aphelenchoides sp. mit 17 verschiedenen Pilzspezies als Nahrungsgrundlage
untersucht. Neben saprophytischen Arten (Agrocybe, Chaetomium) eigneten sich
insbesondere Mykorrhizapilze (Cenococcum, Hymenoscyphus, Laccaria) für eine
Massenvermehrung. Eine schlechte Nahrungsquelle stellten mitosporische
Arten, wie Alternaria, Monocillium oder Penicillium, dar. Dies dürfte auf
toxische Stoffwechselprodukte (z.B., Antibiotika) und/oder auf
morphologische Unterschiede (z.B., Sporenbildung) zurückzuführen sein. Die
gute Vermehrung der Nematoden an Mykorrhizapilzen ist von weitreichender
Bedeutung für das Freiland. Negative Auswirkungen auf die Ausbildung und
Funktion von Mykorrhiza im Boden sind zu erwarten. In
Nahrungswahlexperimenten zeigte Aphelenchoides sp. eine ausgeprägte
Präferenz für bestimmte Pilzarten. Das Wechseln zwischen den einzelnen
Pilzspezies weist auf die Bevorzugung von “Mischnahrung” hin. Dies dürfte
eine Strategie zur Vermeidung von hohen Konzentrationen toxischer
Nahrungsbestandteile sein. Präferenz und Nahrungsqualität standen nur in
geringem Zusammenhang. Somit können auch Pilze, die eine schlechte
Nahrungsquelle darstellen, attraktiv auf Nematoden wirken und deren
Verbreitung in Boden und Rhizosphäre beeinflussen.
Quantitative phase analysis of clay minerals by X-ray powder diffraction using artificial neural networks. I. Feasibility study with calculated powder patterns
Authors: Griffen D. T.
Published: July 2002

An artificial neural network with back-propagation architecture has been applied to the problem of the quantitative analysis of simulated clay mixtures from synthetic X-ray diffraction (XRD) data. A ‘clay characterization function’ (CCF) has been devised that combines information from two clay XRD peaks into a single peak that simplifies the problem which the neural network must solve. In addition, it eliminates peaks from non-layered minerals. A neural network with 17 neurons in the hidden layer and log-sigmoid transfer functions in each layer is sufficiently successful at predicting the compositions of binary and ternary mixtures of the three model clays to demonstrate the potential of the method. Moreover, training is accomplished in relatively short times using a Levenberg-Marquardt algorithm.

Although the problem ‘solved’ by this neural network is rather simple, the approach has the potential for the much more complex problem of the quantitative phase analysis of mixtures of real clay minerals. In this study, only the CCF peak heights have been used, but the positions and peak widths also contain important information. It may be practical to include as variables not only the concentrations of clay phases, but also compositional information to which XRD is sensitive.
Crystal structure of the high-pressure monoclinic phase-II of cristobalite, SiO2
Authors: Dove M. T. , Craig M. S. , Keen D. A. , Marshall W. G. , Redfern S. A. T. , Trachenko K. O. , Tucker M. G.
Published: July 2002

The crystal structure of the high-pressure phase-II of cristobalite has been solved by neutron diffraction (space group P21/c, a = 8.3780(11) Å, b = 4.6018(6) Å, c = 9.0568(13) Å, β = 124.949(7)°, at P = 3.5 GPa). This phase corresponds to a distortion of the high-temperature cubic β-phase, rather than of the ambient temperature and pressure tetragonal α-phase.
Relationships between the medium-range structure of glasses and crystals
Authors: Gaskell P. H.
Published: July 2002

The known structure of a crystalline phase is almost always useful in investigating the unknown structure of the compositionally equivalent glass. For the local environment around elements like Si, B and P, the correspondence between site geometry and symmetry can be impressively close. Beyond near neighbours, any relationship becomes less obvious – at least in real-space data. Progress in understanding the medium-range structures of glasses has been painfully slow as a result. One essential clue is given by reciprocal-space features at low Q (scattering vector) in X-ray or neutron scattering data, which are clearly related to the medium-range structure. Interpretation of these features as ‘quasi-Bragg’ scattering allows direct comparison between the structures of the glass and equivalent crystalline phases. Applications of this method will be illustrated in borates and silicates, together with some chalcogenide glasses. Correspondence between low-Q features for these glasses and compositionally-equivalent crystals is qualitatively good. In some cases there is semi-quantitative agreement too. Thus the essential flavour of the medium-range structure of several typical glasses appears to be interpretable, rather easily.
Okayamalite, Ca2B2SiO7, a new mineral, boron analogue of gehlenite
Authors: Matsubara Satoshi , Miyawaki Ritsuro , Kato Akira , Yokoyama Kazumi , Okamoto Akiyoshi
Published: July 2002

Okayamalite, Ca2B2SiO7, tetragonal,P21m,a= 7.116,c= 4.815 Å, Z = 2, is a new member of melilite group, the boron analogue of gehlenite. Electron microprobe analysis gave CaO 46.28, B2O328.50, SiO224.24, Al2O30.36, total 99.38 wt.%, corresponding to Ca2.01B2.00Si0.98Al0.02O7, a natural counterpart of Ca2B2SiO7known only synthetically. The strongest lines in the X-ray powder diffraction pattern are 3.479 (40)(111), 2.862 (55)(201), 2.654 (100)(211), 2.129 (20)(301), 1.920 (35)(212), 1.644 (29)(312), very close to those of the synthetic material (a= 7.115, andc= 4.812 ). It is creamy white in colour with an earthy appearance due to the fine grain size. Streak white, cleavage not observed. Hardness ∼5½. Density calculated on the ideal formula is 3.30 g/cm3. It is optically uniaxial negative with ω = 1.700, and ɛ = 1.696. It occurs as patches of a few millimetres across in grey homogeneous-looking aggregate of wollastonite, vesuvianite, calcite and johnbaumite from Fuka mine, Bicchu-cho, Okayama Prefecture, Japan. The patches consist of very fine grains of the mineral up to 30 μm. Okayamalite is considered to be a product after the reaction formula: CaCO3+ CaSiO3+ B2O3= Ca2B2SiO7+ CO2, arising from boron metasomatism of a wollastonite-calcite aggregate. The name is for the prefecture.
Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices
Authors: Koolwijk Pieter , Sidenius Nicolai , Peters Erna , Sier Cornelis F. M. , Hanemaaijer Roeland , Blasi Francesco , van Hinsbergh Victor W. M.
Published: July 2002

Pericellular proteolysis plays an important role in cell migration and the formation of new capillary structures. The plasminogen activator/plasmin and matrix degrading metalloproteinase (MMP) cascades act together in the remodeling of matrix and cell-matrix contacts. Previously we have shown that the formation of capillary structures by human foreskin microvascular endothelial cells (hMVECs) in a 3-dimensional fibrin matrix requires a functional urokinase-type plasminogen activator receptor (u-PAR). Here we report on the unexpected finding that inhibition of hMVEC-derived MMP activity by BB94 (batimastat) increased the outgrowth of capillary structures in a fibrin matrix. BB94 prevented the release of the u-PA binding domain D1 of u-PAR and thereby increased the number of functional u-PARs on hMVECs without affecting the u-PAR messenger RNA levels. Comparison of various types of protease inhibitors pointed to the prime involvement of MMP activity. Using recombinant MMPs it was shown that MMP-12 activity was able to release the D1 domain of cellularly expressed u-PAR. In addition, the expression of MMP-12 in control and basic fibroblast growth factor/tumor necrosis factor-α–stimulated hMVECs was shown by reverse transcriptase–polymerase chain reaction, suggesting that endothelial cell–derived MMP-12 may be involved in angiogenesis-related u-PAR shedding. This new mechanism of u-PAR cleavage provides new insights into the mutual interactions between the MMP and u-PA/plasmin systems. Moreover, it may be helpful in the interpretation of recent data on the use of specific MMP inhibitors in the treatment of several types of cancer.
Human polymorphism of P-selectin glycoprotein ligand 1 attributable to variable numbers of tandem decameric repeats in the mucinlike region
Authors: Afshar-Kharghan Vahid , Diz-Küçükkaya Reyhan , Ludwig Erwin H. , Marian Ali J. , López José A.
Published: July 2002

Platelet GP Ibα and leukocyte P-selectin glycoprotein ligand 1 (PSGL-1) are membrane mucins with a number of structural and functional similarities. It was investigated whether, like GP Ibα, PSGL-1 is affected by a variable number of tandem repeat polymorphism in its mucin-like region. By polymerase chain reaction amplification of the genomic region encoding the PSGL-1 repeats, 3 allelic variants were identified in the human population. The 3 alleles—A, B, and C—from largest to smallest, contained 16, 15, and 14 decameric repeats, respectively, with the B variant lacking repeat 2 and the C variant retaining repeat 2 but lacking repeats 9 and 10. Allele frequencies were highest for the A variant and lowest for the C variant in the 2 populations studied (frequencies of 0.81, 0.17, and 0.02 in white persons and 0.65, 0.35, and 0.00 in Japanese). Thus, PSGL-1 is highly polymorphic and contains a structural polymorphism that potentially indicates functional variation in the human population.
Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses
Authors: Wang Xiaosong , Kumanogoh Atsushi , Watanabe Chie , Shi Wei , Yoshida Kanji , Kikutani Hitoshi
Published: July 2002

CD100/Sema4D is a 150-kd transmembrane protein that belongs to the semaphorin family. The interaction of CD100 with CD72 is critical for the immune system. In CD100-deficient mice, the production of specific antibodies against T-cell–dependent antigens is severely impaired, but not against T-cell–independent antigens. Here, a functional soluble CD100 protein (sCD100) released from activated lymphocytes is reported. sCD100 was detected in culture supernatants of activated lymphocytes. Either affinity-purified from supernatants of activated T-cells, or produced as a recombinant sCD100 protein consisting of the extracellular region of the mouse CD100 fused to the human IgG1 Fc (CD100-Fc), sCD100 significantly enhanced CD40-induced B-cell responses. Furthermore, sCD100 was detected either in sera of mice immunized with T-cell–dependent antigens, or in sera of MRL/lpr mice, but not in sera of mice immunized with T-cell–independent antigens. A significant correlation was observed between the level of sCD100 and the titer of autoantibodies in the serum of MRL/lpr mice. This study's findings suggest a potential role for sCD100 in immune responses, including production of antibody, and autoimmune diseases.
High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial
Authors: Horning Sandra J. , Negrin Robert S. , Hoppe Richard T. , Rosenberg Saul A. , Chao Nelson J. , Long Gwynn D. , Brown B. William , Blume Karl G.
Published: July 2002

Advanced stage follicular small cleaved and mixed cell lymphoma is characterized by relapse from remission and survival ranging from 6 to 12 years. Because young patients have the greatest compromise in longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A reference sample of 188 patients of similar age, stage, and histology managed at this institution before 1988 was identified for comparison of patient characteristics and outcomes. Compared with reference patients, transplant recipients had a higher tumor burden at diagnosis. With a median follow-up of 6.5 years, the estimated 10-year survival after transplantation was 86%. There was a single lymphoma death yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten patients relapsed, one with microscopic disease only. High tumor burden at diagnosis and incomplete response to chemotherapy adversely influenced survival in the reference but not in the transplanted patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of whom had high tumor burdens, compares favorably with our observations in appropriately matched reference patients.
Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history
Authors: Bennaceur-Griscelli Annelise , Pondarré Corinne , Schiavon Valérie , Vainchenker William , Coulombel Laure
Published: July 2002

Stem cell proliferation induced by potent cytokines usually leads to a loss of primitive potential through differentiation. In this study, the ability of cytokines and murine MS5 stromal cells to independently regulate the proliferation and long-term culture-initiating cell (LTC-IC) activity of primitive CD34+CD38low/neg human bone marrow cells was evaluated. To compare populations with identical proliferation histories, cells were labeled with carboxy fluorescein diacetate succinimidyl ester, and LTC-IC activity was assessed 4 days later in cells that had accomplished the same number of divisions with or without MS5 cells. MS5 cells counteracted dramatically the loss of LTC-IC activity observed in the presence of cytokines alone. Thus, in the presence of MS5 cells, means of 1233 (n = 5) and 355 (n = 9) LTC-IC–derived colony-forming cells (CFCs) were generated by 1000 cells that performed 3 and 4 divisions respectively, whereas 311 (n = 5) and 64 (n = 5) CFCs were generated by 1000 cells cultured without MS5 cells. Interestingly, MS5 cells had no detectable effect on the LTC-IC activity of cells that divided only twice in 4 days—1606 CFCs (n = 6) and 1993 (n = 6) CFCs, respectively, without and with MS5 cells—and a 48 additional hours of coculture were necessary to unmask changes in the LTC-IC activity mediated by stromal cells. These results indicate that cytokines and stroma-derived signals can regulate independently the proliferation and differentiation of primitive cells and that these stroma-derived extracellular factors act directly on their target cells.
Synthesis, secretion, and subcellular localization of serglycin proteoglycan in human endothelial cells
Authors: Schick Barbara P. , Gradowski Joel F. , Antonio James D. San
Published: July 2002

The serglycin proteoglycan is best known as a hematopoietic cell granule proteoglycan. It has been found that serglycin is synthesized by endothelial cells, is localized to cytoplasmic vesicles, and is constitutively secreted. Serglycin messenger RNA in human umbilical vein endothelial cells (HUVECs) and cultured human aortic endothelial cells was detected by reverse transcription–polymerase chain reaction.35S-sulfate–labeled secreted and intracellular proteoglycans were analyzed. It was found that 85% of the proteoglycans synthesized during culture were secreted. A core protein of the appropriate size for serglycin was detected by analysis of the chondroitinase-digested 35S-sulfate–labeled HUVEC proteoglycans. This was the major core protein of the secreted chondroitin sulfate proteoglycans. Recombinant serglycin core protein was used to generate an antibody in chickens. A core protein identified by Western blotting of chondroitinase digests of HUVEC proteoglycans corresponded to the major 35S-sulfate– labeled core protein. Identical results were obtained with 2 hematopoietic cell lines. Cyto-immunofluorescence showed cytoplasmic vesicular and perinuclear labeling in hematopoietic cells and HUVECs. The serglycin-containing vesicles in HUVECs are distinct from the Weibel-Palade bodies, which contain von Willebrand factor. Confocal microscopy showed that tissue plasminogen activator was distributed similarly to serglycin. Serglycin may be important for the function of these vesicles and, once secreted, for the modulation of the activity of their constituents.
CD4+ cutaneous T-cell lymphoma cells express the p140–killer cell immunoglobulin-like receptor
Authors: Bagot Martine , Moretta Alessandro , Sivori Simona , Biassoni Roberto , Cantoni Claudia , Bottino Cristina , Boumsell Laurence , Bensussan Armand
Published: July 2002

Tumor cells of patients with cutaneous T-cell lymphoma (CTCL) have the cell surface phenotype of mature T-helper lymphocytes, and it may be impossible to differentiate them from nonmalignant lymphocytes in skin and blood. Until now, no specific cell membrane marker of CTCL has been reported. In the current study, it is reported for the first time that CTCL cells express the major histocompatibility complex class I binding p140–killer cell immunoglobulin-like receptor, which has been described on a minor subset of natural killer lymphocytes and on a marginal circulating CD8+ T lymphocyte subset. Interestingly, the molecular characterization of this KIR expressed by CTCL allowed us to isolate a novel allelic form of p140–KIR3DL, resulting in 4 amino acid substitutions, 3 in the extracellular immunoglobulin-like domain of the protein and one in the cytoplasmic region. This finding is likely to be important both for the pathophysiology and for the clinical treatment of patients with CTCL.
Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis
Authors: Yamada Yoshihiro , Takakura Nobuyuki , Yasue Hirofumi , Ogawa Hisao , Fujisawa Hajime , Suda Toshio
Published: July 2002

Neuropilin 1 (NP-1) is a receptor for vascular endothelial growth factor (VEGF) 165 (VEGF165) and acts as a coreceptor that enhances VEGF165 function through tyrosine kinase VEGF receptor 2 (VEGFR-2). Transgenic overexpression of np-1results in an excess of capillaries and blood vessels and a malformed heart. Thus, NP-1 may have a key role in vascular development. However, how NP-1 regulates vascular development is not well understood. This study demonstrates how NP-1 can regulate vasculogenesis and angiogenesis in vitro and in vivo. In homozygous np-1mutant (np-1−/−) murine embryos, vascular sprouting was impaired in the central nervous system and pericardium. Para-aortic splanchnopleural mesoderm (P-Sp) explants fromnp-1−/− mice also had vascular defects in vitro. A monomer of soluble NP-1 (NP-1 tagged with Flag epitope) inhibited vascular development in cultured wild-type P-Sp explants by sequestering VEGF165. In contrast, a dimer of soluble NP-1 (NP-1 fused with the Fc part of human IgG) enhanced vascular development in cultured wild-type P-Sp explants. Moreover, the NP-1–Fc rescued the defective vascular development in culturednp-1−/− P-Sp explants. A low dose of VEGF alone did not promote phosphorylation of VEGFR-2 on endothelial cells from np-1−/− embryos, but simultaneous addition of a low dose of VEGF and NP-1–Fc phosphorylated VEGFR-2 significantly. Moreover, NP-1–Fc rescued the defective vascularity of np-1−/− embryos in vivo. These results suggest that a dimer form of soluble NP-1 delivers VEGF165 to VEGFR-2–positive endothelial cells and promotes angiogenesis.
Bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase II deficiency syndrome
Authors: McMahon Corrina , Will Andrew , Hu Peiyi , Shah Gul N. , Sly William S. , Smith Owen P.
Published: July 2002

Carbonic anhydrase II (CAII), found in renal tubules, brain, and osteoclasts, is critical in acid-base homeostasis and bone remodeling. Deficiency of CAII gives rise to a syndrome of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification with associated developmental delay. It is inherited in an autosomal recessive fashion and found most frequently in the Mediterranean region and the Middle East. We report 2 related Irish families with clinically severe CAII deficiency in whom the gene mutation has been fully elucidated. Two children, one from each family, have undergone allogeneic bone marrow transplantation because of severe progressive visual and hearing loss. The older 2 children had already developed cerebral calcification and marked visual loss at the time of diagnosis and were treated symptomatically. Post-transplantation evaluation at 2 and 3 years demonstrates histologic and radiologic resolution of their osteopetrosis with stabilization of hearing and vision. Both children remain developmentally delayed and continue to have RTA, and the older child has now developed cerebral calcification. Allogeneic bone marrow stem cell replacement cures the osteoclast component of CAII deficiency and retards the development of cerebral calcification, but it appears to have little or no effect on the renal lesions.
Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches
Authors: Nilsson Susan K. , Johnston Hayley M. , Coverdale Judi A.
Published: July 2002

The spatial distribution of subpopulations of hemopoietic progenitor cells following syngeneic transplantation was investigated at the single-cell level. The location of infused hemopoietic progenitor cells within the femoral bone marrow of nonablated recipients was determined by 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester labeling of cells and in situ fixation by perfusion. Analysis performed over 15 hours after infusion demonstrated that the spatial distribution of transplanted marrow cells is not a random process. Although the majority of cells enter the bone marrow from the central marrow vessels, the subsequent localization within the bone marrow varied according to their phenotype. Candidate “stem cells” demonstrated selective redistribution and were significantly enriched within the endosteal region, whereas mature terminally differentiated and lineage-committed cells selectively redistributed away from the endosteal region and were predominantly in the central marrow region. Together, these data strongly support historical evidence of the presence of endosteal hemopoietic stem cell niches.
Defective binding of factor XI–N248 to activated human platelets
Authors: Sun Mao-Fu , Baglia Frank A. , Ho David , Martincic Danko , Ware Russell E. , Walsh Peter N. , Gailani David
Published: July 2002

Variants of factor XI containing Gln226 to Arg (Q226 to R) and Ser248 to Asn (S248 to N) substitutions were first identified in an African American family with a history of excessive bleeding. The substitutions have recently been identified in unrelated individuals, suggesting they are relatively common. Both amino acids are located in the third apple domain of factor XI, an area implicated in binding interactions with factor IX and activated platelets. Recombinant factor XI–R226 and factor XI–N248 were compared with wild-type factor XI in assays for factor IX activation or platelet binding. Factor XI–R226 activates factor IX with a Michaelis-Menten constant (Km) about 5-fold greater than wild-type protein. The catalytic efficiency of factor IX activation is similar to wild-type protein, however, due to an increase in the turnover number (kcat) for the reaction. Iodinated factor XI–N248 binds to activated platelets with a dissociation constant (Kd) more than 5-fold higher than wild-type protein (55 nM and 10 nM, respectively). Activation of factor XI–N248 by thrombin in the presence of activated platelets is slower and does not progress to the same extent as activation of the wild-type protein under similar conditions. Factor XI–N248 activates factor IX normally in a purified protein system and has relatively normal activity in activated partial thromboplastin time (aPTT) assays. Factor XI–N248 is the first factor XI variant described with a clear functional difference compared with wild-type protein. Importantly, the defect in platelet binding would not be detected by routine clinical evaluation with an aPTT assay.
Expression of CCR-7, MIP-3β, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities
Authors: Parlato Stefania , Santini Stefano M. , Lapenta Caterina , Di Pucchio Tiziana , Logozzi Mariantonia , Spada Massimo , Giammarioli Anna Maria , Malorni Walter , Fais Stefano , Belardelli Filippo
Published: July 2002

The migration capability of dendritic cells (DCs) is regulated by their response to factors, namely chemokines, that characterize maturation stage and shape their functional activities. This study examines the morphology, expression of chemokines/chemokine receptors, and migration properties of DCs generated after treatment of monocytes with type I interferon (IFN) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (IFN-DCs). IFN-DCs showed phenotypical and morphologic features undetectable in DCs generated in the presence of interleukin 4 (IL-4) and GM-CSF, such as expression of CD83 and CD25 and the presence of CD44+, highly polarized, thin, and long dendrites. IFN-DCs markedly migrated in response to β-chemokines (especially MIP-1β) and expressed the Th-1 chemokine IP-10. Notably, IFN-DCs showed an up-regulation of CCR7 as well as of its natural ligand MIP-3β, characteristics typical of mature DCs. Of interest, IFN-DCs exhibited a marked chemotactic response to MIP-3β in vitro and strong migratory behavior in severe combined immunodeficient (SCID) mice. In SCID mice reconstituted with human peripheral blood leukocytes, IFN-DCs induced a potent primary human antibody response and IFN-γ production, indicative of a Th-1 immune response. These results define the highly specialized maturation state of IFN-DCs and point out the existence of a “natural alliance” between type I IFN and monocyte/DC development, instrumental for ensuring an efficient connection between innate and adaptive immunity.
Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation
Authors: Bach Peter B. , Schrag Deborah , Nierman David M. , Horak David , White Peter , Young James W. , Groeger Jeffrey S.
Published: July 2002

Patients who develop respiratory failure requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT) have very high mortality. Several investigators have identified prognostic features that can be used to identify a subset of these patients who are virtually certain to die, yet these have never been prospectively assessed. The objectives of this study were to determine the accuracy of published prognostic features for mortality and to determine the survival of patients who recover from respiratory failure. A systematic review of the literature was undertaken to identify reported poor prognostic features and survival rates. The study validated the reported poor prognostic features on a prospective, multicenter inception cohort of 226 patients with respiratory failure requiring mechanical ventilation after HSCT. The main outcome measures were determination of a baseline probability of death, drawn from literature review; likelihood ratio of mortality for each prognostic feature determined from the validation cohort; conditional probability of death in the presence of each feature; and 6-month survival of those who recover. Patients requiring mechanical ventilation after HSCT have a baseline probability of death of 82% to 96%. In the setting of combined hepatic and renal dysfunction, the probability of death rises to 98% to 100%. Other previously reported prognostic features are less strongly associated with mortality. For patients who recover from respiratory failure, the proportion surviving 6 months or longer ranges from 27% to 88%. It was concluded that in patients requiring mechanical ventilation after HSCT, the presence of combined hepatic and renal dysfunction is highly predictive of death. The presence of this feature may justify the recommendation to withdraw life-sustaining measures.
Origins of “late” relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes
Authors: Ford Anthony M. , Fasching Karin , Panzer-Grümayer E. Renate , Koenig Margit , Haas Oskar A. , Greaves Mel F.
Published: July 2002

Approximately 20% of childhood B-precursor acute lymphoblastic leukemia (ALL) has a TEL-AML1 fusion gene, often in association with deletions of the nonrearranged TEL allele.TEL-AML1 gene fusion appears to be an initiating event and usually occurs before birth, in utero. This subgroup of ALL generally presents with low- or medium-risk features and overall has a very good prognosis. Some patients, however, do have relapses late or after the cessation of treatment, at least on some therapeutic protocols. They usually achieve sustained second remissions. Posttreatment relapses, or even very late relapses (5-20 years after diagnosis), in childhood ALL are clonally related to the leukemic cells at diagnosis (by IGH or T-cell receptor [TCR] gene sequencing) and are considered, therefore, to represent a slow re-emergence or escape of the initial clone seen at diagnosis. Microsatellite markers and fluorescence in situ hybridization identified deletions of the unrearranged TEL allele and IGH/TCR gene rearrangements were analyzed; the results show that posttreatment relapse cells in 2 patients with TEL-AML1–positive ALL were not derived from the dominant clone present at diagnosis but were from a sibling clone. In contrast, a patient who had a relapse while on treatment with TEL-AML1 fusion had essentially the sameTEL deletion, though with evidence for microsatellite instability 5′ of TEL gene deletion at diagnosis, leading to extended 5′ deletion at relapse. It is speculated that, in some patients, combination chemotherapy for childhood ALL may fail to eliminate a fetal preleukemic clone with TEL-AML1 and that a second, independent transformation event within this clone after treatment gives rise to a new leukemia masquerading as relapse.