bluuebunny/crossref_metadata_2025 huggingface dataset:
THE QUANTUM KNIZHNIK–ZAMOLODCHIKOV EQUATION ASSOCIATED WITH $U_q(A_2^{(2)})$ FOR |q| = 1
Authors: KOJIMA TAKEO
Published: January 2003

We present an integral representation to the quantum Knizhnik–Zamolodchikov equation associated with twisted affine symmetry [Formula: see text] for massless regime |q| = 1. Upon specialization, it leads to a conjectural formula for the correlation function of the Izergin–Korepin model in massless regime |q| = 1. In a limiting case q → -1, our conjectural formula reproduce the correlation function for the Izergin–Korepin model1,2 at critical point q = -1.
CONTRACTION OF THE FINITE RADIAL OSCILLATOR
Authors: ATAKISHIYEV NATIG M. , POGOSYAN GEORGE S. , WOLF KURT BERNARDO
Published: January 2003

The finite radial oscillator model, introduced in [J. Phys.A34, 9399–9415 (2001)], is based on the precontracted dynamical algebra so4, consisting of two position and two momentum operators, total mode number and angular momentum, all with a finite number of eigenvalues. We examine the contraction of this model to the ordinary radial quantum oscillator as the number and density of points increase. This is done on the level of the dynamical algebra, of the Schrödinger difference equation, and of the wave functions.
Local compactness in approach spaces II
Authors: Lowen R. , Verbeeck C.
Published: January 2003

This paper studies the stability properties of the concepts of local compactness introduced by the authors in 1998. We show that all of these concepts are stable for contractive, expansive images and for products.
Multilocal invariants for the classical groups
Authors: Dhooghe Paul F.
Published: January 2003

Multilocal higher‐order invariants, which are higher‐order
invariants defined at distinct points of representation space,
for the classical groups are derived in a systematic way. The
basic invariants for the classical groups are the well‐known
polynomial or rational invariants as derived from the Capelli
identities. Higher‐order invariants are then constructed from the
former ones by means of total derivatives. At each order, it
appears that the invariants obtained in this way do not generate
all invariants. The necessary additional invariants are
constructed from the invariant polynomials on the Lie algebra of
the Lie transformation groups.
On the convolution product of the distributional kernel Kα,β,γ,ν
Authors: Kananthai A. , Suantai S.
Published: January 2003

We introduce a distributional kernel Kα,β,γ,ν which is related to the operator ⊕ k iterated k
times and defined by , where p + q = n is the dimension of the space ℝ n of the n‐dimensional Euclidean space, x = (x1, x2, …, xn) ∈ ℝ n, k is a nonnegative integer, and α, β, γ, and ν are complex parameters. It is found that the existence of
the convolution is depending on the conditions of p and q.
Asymptotic almostperiodicity of C‐semigroups
Authors: Xie Linghong , Li Miao , Huang Falun
Published: January 2003

Let {T(t)}t≥0 be a C‐semigroup on a Banach space X with generator A. We will investigate the asymptotic almost periodicity of {T(t)}
via the Hille‐Yosida
space of its generator.
An improved Bayes empirical Bayes estimator
Authors: Karunamuni R. J. , Prasad N. G. N.
Published: January 2003

Consider an experiment yielding an observable random quantity X
whose distribution Fθ
depends on a parameter θ
with θ being distributed according to some distribution
G0. We study the Bayesian estimation problem of θ
under squared error loss function based on X, as well as some
additional data available from other similar experiments
according to an empirical Bayes structure. In a recent paper,
Samaniego and Neath (1996) investigated the questions of whether,
and when, this information can be exploited so as to provide a
better estimate of θ in the current experiment.
They constructed a Bayes empirical Bayes estimator that
is superior to the original Bayes estimator, based only on the
current observation X for sampling situations involving
exponential families‐conjugate prior pair. In this paper, we
present an improved Bayes empirical Bayes estimator having a
smaller Bayes risk than that of Samaniego and Neath′s estimator.
We further observe that our estimator is superior to the original
Bayes estimator in more general situations than those of the
exponential families‐conjugate prior combination.
Local stability of the additive functional equation and its applications
Authors: Jung Soon-Mo , Kim Byungbae
Published: January 2003

The main purpose of this paper is to prove the Hyers‐Ulam
stability of the additive functional equation for a large class of unbounded domains. Furthermore, by using the theorem, we prove the stability of Jensen′s functional equation for a large class of restricted domains.
Equivariant embeddings and compactifications of free G‐spaces
Authors: Antonyan Natella
Published: January 2003

For a compact Lie group G, we characterize free G‐spaces that admit free G‐compactifications. For such G‐spaces, a universal compact free G‐space of given weight and given dimension is constructed. It is shown that if G is finite, the n‐dimensional Menger free G‐compactum μ n is universal for all separable, metrizable free G‐spaces of dimension less than or equal to n. Some of these results are extended to the case of G‐spaces with a single orbit type.
Mirror symmetry for concavex vector bundles on projective spaces
Authors: Elezi Artur
Published: January 2003

Let X ⊂ Y be smooth, projective manifolds. Assume that
ι : X → ℙs is the zero locus of a generic section of V+ = ⊕i∈I𝒪(ki), where all the ki′s are positive. Assume furthermore that 𝒩X/Y = ι∗(V−), where V− = ⊕j∈J𝒪(−lj) and all the lj′s are negative. We show that under appropriate restrictions, the generalized Gromov‐Witten invariants of X inherited from Y can be calculated via a modified Gromov‐Witten
theory on ℙs. This leads to local mirror symmetry on the A‐side.
Boundedness for multilinear Marcinkiewicz operators on certain Hardy spaces
Authors: Lanzhe Liu
Published: January 2003

The boundedness for the multilinear Marcinkiewicz operators on
certain Hardy and Herz‐Hardy spaces are obtained.
Matrix measure and application to stability of matrices and interval dynamical systems
Authors: Zahreddine Ziad
Published: January 2003

Using some properties of the matrix measure, we obtain a general
condition for the stability of a convex hull of matrices that
will be applied to study the stability of interval dynamical
systems. Some classical results from stability theory are
reproduced and extended. We present a relationship between the
matrix measure and the real parts of the eigenvalues that make it
possible to obtain stability criteria.
A note on some applications of α‐open sets
Authors: Caldas Miguel
Published: January 2003

The object of this note is to introduce and study topological
properties of α‐derived, α‐border, α‐frontier, and α‐exterior of a set using the concept of α‐open sets. Moreover, we study some further properties of the well‐known notions of α‐closure and α‐interior. We also obtain a new decomposition of
α‐continuous functions.
Vector fields on nonorientable surfaces
Authors: Barza Ilie , Ghisa Dorin
Published: January 2003

A one‐to‐one correspondence is established between the germs of
functions and tangent vectors on a NOS X
and the
bi‐germs of functions, respectively, elementary fields of tangent
vectors (EFTV) on the orientable double cover of X.
Some representation theorems for the algebra of germs of
functions, the tangent space at an arbitrary point of
X, and the space of vector fields on X are proved by using a symmetrisation process. An example related to the normal derivative on the border of the Möbius strip supports the nontriviality of the concepts introduced in this paper.
The dilatation invariant in the homotopy of spheres
Authors: Xu Senlin , Lv Jinchi
Published: January 2003

We get some results on the filtration invariant in the homotopy
of spheres. Then by the relation between the dilatation invariant
and filtration invariant, we get the corresponding results on the
dilatation invariant in the homotopy of spheres.
Plato's Division of Goods in the Republic
Authors: Heinaman Robert
Published: January 2003

In the Republic Plato draws a distinction among goods between (1) those that are good in themselves but not good for their consequences, (2) those that are good both in themselves and for their consequences, and (3) those that are not good in themselves but are good for their consequences. This paper presents an interpretation of this classification, in particular its application to the case of justice. It is argued that certain causal consequences of justice as well as factors that are not causal consequences of justice are relevant in explaining why justice is good in itself; and that it is only the reputation for justice and the causal consequences that follow from that reputation that are relevant in explaining why it is good for its consequences.
Aristotle on the Akratic's Knowledge
Authors: Grgić Filip
Published: January 2003

This paper is an analysis of Aristotle's Nicomachean Ethics 7.3. Aristotle's discussion in this chapter is motivated by the Socratic doctrine, elaborated in Plato's Protagoras, according to which it is impossible to know what is good and act against this knowledge. Aristotle wants to rebut this doctrine and show that there is a sense of "know" such that this is possible. I argue that this is all that he wants to do in EN 7.3, and that his discussion is not meant to provide an explanation of akrasia, as is usually supposed by commentators. Since the akratic knows that the action she is performing is not good for her, and actions are particulars, the akratic's knowledge is about a particular. I argue that Aristotle's discussion in EN 7.3 adds strength to the idea that knowledge of a particular is explainable only in terms of knowledge of a universal. More determinately, knowledge of a particular is explainable in terms of the actualization or use of knowledge of a universal, and such an actualization is in turn explainable by means of the syllogistic form. Thus, I argue that syllogisms in 7.3 (esp. at 1146b35-1147a10) are not "practical syllogisms", but that their function is epistemological: they are meant to reveal the structure and content of the akratic's knowledge, not to explain her actions.
The Development of Modus Ponens in Antiquity : From Aristotle to the 2nd Century AD
Authors: Bobzien Susanne
Published: January 2003

'Aristotelian logic', as it was taught from late antiquity until the 20th century, commonly included a short presentation of the argument forms modus (ponendo) ponens, modus (tollendo) tollens, modus ponendo tollens, and modus tollendo ponens. In late antiquity, arguments of these forms were generally classified as 'hypothetical syllogisms'. However, Aristotle did not discuss such arguments, nor did he call any arguments 'hypothetical syllogisms'. The Stoic indemonstrables resemble the modus ponens/tollens arguments. But the Stoics never called them 'hypothetical syllogisms'; nor did they describe them as ponendo ponens, etc. The tradition of the four argument forms and the classification of the arguments as hypothetical syllogisms hence need some explaining. In this paper, I offer some explanations by tracing the development of certain elements of Aristotle's logic via the early Peripatetics to the logic of later antiquity. I consider the questions: How did the four argument forms arise? Why were there four of them? Why were arguments of these forms called 'hypothetical syllogisms'? On what grounds were they considered valid? I argue that such arguments were neither part of Aristotle's dialectic, nor simply the result of an adoption of elements of Stoic logic, but the outcome of a long, gradual development that begins with Aristotle's logic as preserved in his Topics and Prior Analytics; and that, as a result, we have a Peripatetic logic of hypothetical inferences which is a far cry both from Stoic logic and from classical propositional logic, but which sports a number of interesting characteristics, some of which bear a cunning resemblance to some 20th century theories.
The Cyrenaics on Pleasure, Happiness, and Future-Concern
Authors: O'Keefe Tim
Published: January 2003

The Cyrenaics assert that (1) particular pleasure is the highest good, and happiness is valued not for its own sake, but only for the sake of the particular pleasures that compose it; (2) we should not forego present pleasures for the sake of obtaining greater pleasure in the future. Their anti-eudaimonism and lack of future-concern do not follow from their hedonism. So why do they assert (1) and (2)? After reviewing and criticizing the proposals put forward by Annas, Irwin and Tsouna, I offer two possible reconstructions. In the first reconstruction, I explain claim (1) as follows: happiness has no value above and beyond the value of the particular pleasures that compose it. Also, there is no "structure" to happiness. The Cyrenaics are targeting the thesis that happiness involves having the activities of one's life forming an organized whole, the value of which cannot be reduced to the value of the experiences within that life. I explain claim (2) as follows: a maximally pleasant life is valuable, but the best way to achieve it is to concentrate heedlessly on the present. In the second reconstruction, the good is radically relativized to one's present preferences. The Cyrenaics assert that we desire some particular pleasure, e.g., the pleasure that results from having this drink now. Thus, our telos - which is based upon our desires - is this particular pleasure, not (generic) 'pleasure' or the maximization of pleasure over our lifetime. As our desires change, so does our telos. I conclude that the scanty texts we have do not allow us to decide conclusively between these reconstructions, but I give some reasons to support the second over the first.
Growth cycle of the marbled newt (Triturus marmoratus) in the Mediterranean region assessed by skeletochronology
Authors: Jakob Christiane , Seitz Alfred , Miaud Claude , Crivelli Alain
Published: January 2003

We studied growth patterns within a marbled newt population (Triturus marmoratus, Urodela) at the southeastern limit of its geographical range by skeletochronology of the phalanges and humeri. Seasonal and annual changes in growth rates were assessed through the analyses of 56 females, 66 males and 34 juveniles sampled in different seasons and years. Age and growth cycles were estimated by cross sections of the diaphyseal region of the bone. These analyses revealed a clear line of metamorphosis caused by the metamorphic process itself and the transition to the terrestrial environment. A line of arrested growth (LAG) was observed in winter in both juveniles and adults. Another LAG was recorded in summer among adults. These growth patterns corroborated field observations on life-history traits of the population under study, but differ from those reported for the marbled newt in other environments.
Molecular phylogeny of the salamandrid genus Neurergus: evidence for an intrageneric switch of reproductive biology
Authors: Öz Mehmet , Tautz Diethard , Steinfartz Sebastian , Hwang Ui Wook , Veith Michael
Published: January 2003

A molecular phylogeny of the salamandrid genus Neurergus was reconstructed based on two sections of the 12S and 16S mitochondrial ribosomal genes (810 bp), 19 allozyme and three plasma protein loci. When representative species of all closely related salamandrid groups were included, mitochondrial data provided evidence for monophyly of Neurergus within the Salamandridae. Mitochondrial and allozyme data showed homogenous intrageneric tree topologies, but different estimates of times of separation. We calibrated the evolutionary rate to 0.46% pairwise sequence divergence per million years. Accordingly Neurergus diverged 18 million years ago (mya) from a lineage that comprised Euproctus asper and large bodied newts of the genus Triturus. A split around 11 mya produced two major clades within Neurergus. Further separation within the southern 'N. crocatus-clade' (comprising N. crocatus, N. microspilotus and N. kaiseri) occurred ca. 5 mya. The northern 'N. strauchii-clade' separated into N. s. strauchii and N. s. barani ca. 3 mya. Our molecular phylogeny indicates that stream-reproduction is the ancestral state for Neurergus, adaptations to pond-reproduction in N. kaiseri are the result of an evolutionary switch of reproductive biology within the 'N. crocatus-clade'.
Hatching dynamics and bet-hedging in a temperate frog, Pseudophryne australis (Anura: Myobatrachidae)
Authors: Mahony Michael , Thumm Karen
Published: January 2003

Embryonic development to the time of hatching was found to vary within and between clutches of the red crowned toadlet, Pseudophryne australis. Hatching occurred over many developmental stages, from 24 to 36 (modified Gosner stage). The time taken from oviposition to hatching varied from 15 days to 119 days. In order to determine whether hatching is triggered by environmental cues or is constitutive, clutches were held under constant conditions and compared with those held under conditions similar to the field. Hatching was staggered in all cases implying a constitutive basis. We postulate that this diversification of phenotypes in P. australis is a bet-hedging strategy driven by the unpredictable rainfall conditions within the range of the species. Die Entwicklung der Embryonen des australischen Frosches Pseudophryne australis bis zum Schlüpfen variierte innerhalb und zwischen Gelegen. Das Schlüpfen trat bei vielen Entwicklungsstadien ein. Der Zeitverlauf bis zum Schlüpfen variierte zwischen 15 und 119 Tagen. Gelege wurden unter konstanten Bedingungen gehalten und mit Gelegen in natürlichen Bedingungen verglichen, um festzustellen, ob das Schlüpfen durch Umweltreize angeregt wird, oder ob das Schlüpfen konstitutiv ist. Da das Schlüpfen in allen Behandlungen versetzt war, wird vermutet, dass das Schlüpfverhalten konstitutiv ist. Wir postulieren, dass die Verschiedenartigkeit der Phänotypen bei Pseudophryne australis eine vorbeugende Strategie ist, die durch die nicht voraussagbaren Niederschlagsverhältnisse im Verbreitungsgebiet der Art bedingt wird.
A new species of frog, genus Sooglossus (Anura, Sooglossidae) from Silhouette Island, Seychelles
Authors: Willi Johanna , Gerlach Justin
Published: January 2003

A new species of frog of the genus Sooglossus (Sooglossidae) is described. The family is restricted to Mahé and Silhouette islands in Seychelles. Three species have been described previously (Nesomantis thomasseti, Sooglossus sechellensis and S. gardineri), all found on both islands. A new species is described from Silhouette island; it is associated with the Seychelles endemic palm tree Phoenicophorium borsigianum.
Podarcis carbonelli Pérez-Mellado, 1981 is a distinct species
Authors: Harris D. James , Sá-Sousa Paulo
Published: January 2003

Podarcis carbonelli is considered a full species on the basis of its morphological and genetic divergence from P. bocagei and P. hispanica. Podarcis carbonelli differs from P. bocagei in all twelve biometric variables compared and also in chromatic patterns. Podarcis carbonelli diverges from P.bocagei by more than 13% between cytochrome b sequences (mitochondrial DNA), a value typically reported between congeneric reptile species. Biogeographical criteria also support this hypothesis, as both lizard forms have different distribution ranges with a limited parapatric zone of contact without morphological intermediates.
Varanid combat: perspectives from game theory
Authors: Eason Perri , Attum Omar , Earley Ryan
Published: January 2003

Most data on aggressive encounters in varanid lizards are qualitative and often anecdotal. The few quantitative reports have not explicitly tested the predictions generated by game theoretical models of animal combat despite their apparent relevance. The goal of this paper was to investigate whether the patterns evident in varanid contests conform to the predictions of the sequential assessment game with special emphasis on the organization, duration, and outcome of the encounters. Several characteristics of monitor combat are consistent with the sequential assessment game. For instance, contests are organized into distinct phases, displays are repeated within each phase, and asymmetries play a crucial role in determining contest duration and outcome. However, data pertaining to a number of the sequential assessment game's most critical postulations are absent from the current varanid literature (e.g. the consistency of display intensity within each phase). As more quantitative data emerge, the applicability of the sequential assessment game to varanid contests may be better assessed.
The feeding behavior of the snail-eating snake Pareas carinatus Wagler 1830 (Squamata: Colubridae)
Authors: Götz Matthias
Published: January 2003

The behavior of captive Pareas carinatus feeding on European round-shelled snails is described. The snake bites into the snail's body and lifts it from the ground. With alternate retraction movements of the mandibles, it pulls the body out of the shell while the upper jaw rests on the outside of the shell. There are only slight differences to dipsadine snakes: Pareas never followed a mucus track and did not coil around the snail's shell. There seemed to be a preference to catch the snails from behind. Extraction time (24-390 s) and number of mandibular movements (22-98) were similar to the data on the dipsadines.
Reproductive biology of the false coral snake Oxyrhopus guibei (Colubridae) from southeastern Brazil
Authors: Marques Otavio , Pizzatto Lígia
Published: January 2003

The reproductive biology of the false coral snake, Oxyrhopus guibei, was studied through dissection of 496 specimens, combined with observations on captive individuals. Males mature with smaller body size than females, females attain much larger body size, and male-male combat is not expected. Clutch size ranged from 3 to 20, and was correlated with female length. Reproductive cycles in both males and females seem to be continuous, with vitellogenesis and spermatogenesis occurring throughout the year. Reproductive activity in both sexes decreased at the end of the rainy season possibly due to previous intense reproductive activity in more favorable climatic conditions. The smaller number of individuals collected at the end of the rainy season apparently occurs due to the decrease of reproductive activity of this snake.
Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation
Authors: Norman Keith E. , Cotter Matthew J. , Stewart James B. , Abbitt Kate B. , Ali Majid , Wagner Bart E. , Wallace William A. H. , Forlow S. Bradley , Hellewell Paul G.
Published: January 2003

Widespread microvascular injury followed by vessel obstruction may lead to disseminated intravascular coagulation (DIC). We describe a murine model wherein leukocytes interacting with inflamed microvessels in vivo are activated by antibodies. Treatment of tumor necrosis factor α (TNF-α)–primed mice with anti–Ly-6G antibodies reproduced many of the features of septic or traumatic shock including microvessel obstruction and coagulation, severe vasculitis, respiratory difficulties, and vascular leakage. Mice lacking either E-selectin or P-selectin were protected from this reaction as were animals treated with a combination of either selectin-blocking antibodies and heparin or a selectin antagonist plus heparin. Combined blockade of leukocyte/platelet adhesion and coagulation may provide convincing protection in DIC.
Necessity of tyrosine 719 and phosphatidylinositol 3′-kinase–mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation
Authors: Hashimoto Koji , Matsumura Itaru , Tsujimura Tohru , Kim Dae-Ki , Ogihara Hideki , Ikeda Hirokazu , Ueda Shuji , Mizuki Masao , Sugahara Hiroyuki , Shibayama Hirohiko , Kitamura Yukihiko , Kanakura Yuzuru
Published: January 2003

Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KITVal814) are not fully understood. To examine the oncogenic signal transduction of KITVal814, we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KITVal814 or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KITVal814- derived mutants, KITVal814-Tyr719Phe and KITVal814-Delseverely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3′-kinase (p85PI3-K). Moreover, KITVal814-Tyr719Pheand KITVal814-Del failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85PI3-K, and the C-terminal region are indispensable for factor-independent growth by KITVal814. Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KITWT), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KITWT. Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KITVal814. These results demonstrate that Tyr719 is crucial for constitutive activation of KITVal814, but not for the ligand-induced activation of KITWT, and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KITVal814, thereby suggesting that KITVal814 is a unique activating mutation that leads to a distinguishable function from the effects of KITWT.
Aberrant iron accumulation and oxidized status of erythroid-specific δ-aminolevulinate synthase (ALAS2)–deficient definitive erythroblasts
Authors: Harigae Hideo , Nakajima Osamu , Suwabe Naruyoshi , Yokoyama Hisayuki , Furuyama Kazumichi , Sasaki Takeshi , Kaku Mitsuo , Yamamoto Masayuki , Sassa Shigeru
Published: January 2003

Alas2 encodes the erythroid-specific δ-aminolevulinate synthase (ALAS2 or ALAS-E), the first enzyme in heme biosynthesis in erythroid cells. Mice with theAlas2-null phenotype showed massive cytoplasmic, but not mitochondrial, iron accumulation in their primitive erythroblasts. Because these animals died by day 11.5 in utero, studies of iron metabolism in definitive erythroblasts were not possible using the in vivo model. In this study, embryonic stem (ES) cells lacking theAlas2 gene were induced to undergo differentiation to the definitive erythroblast stage in culture, and the phenotype ofAlas2-null definitive erythroblasts was examined.Alas2-null definitive erythroblasts cell pellets were entirely colorless due to a marked deficiency of heme, although their cell morphology was similar to that of the wild-type erythroblasts. The level of expression of erythroid-specific genes inAlas2-null definitive erythroblasts was also similar to that of the wild-type erythroblasts. These findings indicate thatAlas2-null definitive erythroblasts developed to a stage similar to that of the wild-type erythroblasts, which were also shown to be very similar to the bone marrow erythroblasts in vivo. In contrast, Alas2-null definitive erythroblasts contained 15 times more nonheme iron than did the wild-type erythroblasts, and electron microscopy found this iron to be distributed in the cytoplasm but not in mitochondria. Consistent with the aberrant increase in iron,Alas2-null definitive erythroblasts were more peroxidized than wild-type erythroblasts. These findings suggest that ALAS2 deficiency itself does not interfere with the development of definitive erythroid cells, but it results in a profound iron accumulation and a peroxidized state in erythroblasts.
The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development
Authors: Schotte Remko , Rissoan Marie-Clotilde , Bendriss-Vermare Nathalie , Bridon Jean-Michel , Duhen Thomas , Weijer Kees , Brière Francine , Spits Hergen
Published: January 2003

Human plasmacytoid dendritic cells (pDCs), also called type 2 dendritic cell precursors or natural interferon (IFN)–producing cells, represent a cell type with distinctive phenotypic and functional features. They are present in the thymus and probably share a common precursor with T and natural killer (NK) cells. In an effort to identify genes that control pDC development we searched for genes of which the expression is restricted to human pDC using a cDNA subtraction technique with activated monocyte-derived DCs (Mo-DCs) as competitor. We identified the transcription factor Spi-B to be expressed in pDCs but not in Mo-DCs. Spi-B expression in pDCs was maintained on in vitro maturation of pDCs. Spi-B was expressed in early CD34+CD38− hematopoietic progenitors and in CD34+CD1a− thymic precursors. Spi-B expression is down-regulated when uncommitted CD34+CD1a− thymic precursors differentiate into committed CD34+CD1a+ pre-T cells. Overexpression of Spi-B in hematopoietic progenitor cells resulted in inhibition of development of T cells both in vitro and in vivo. In addition, development of progenitor cells into B and NK cells in vitro was also inhibited by Spi-B overexpression. Our results indicate that Spi-B is involved in the control of pDC development by limiting the capacity of progenitor cells to develop into other lymphoid lineages.
In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas
Authors: Manches Olivier , Lui Gabrielle , Chaperot Laurence , Gressin Rémy , Molens Jean-Paul , Jacob Marie-Christine , Sotto Jean-Jacques , Leroux Dominique , Bensa Jean-Claude , Plumas Joël
Published: January 2003

To assess the sensitivity of primary non-Hodgkin lymphoma cells to rituximab-mediated cytotoxicity, we compared the potency of several rituximab-mediated killing mechanisms on fresh lymphoma cells. All lymphoma cells tested were equally sensitive to antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated phagocytosis of tumor cells, and rituximab-induced apoptosis. However, they were differentially lysed by complement-dependent cytotoxicity (CDC). We found that taking into account both CD20 and complement regulatory protein expression on tumor cells could predict CDC sensitivity in vitro. Importantly, the sensitivity of lymphoma cells to CDC was consistent with the reported different clinical response rates of lymphomas: rituximab induced high CDC killing of follicular lymphoma cells, whereas mantle cell lymphoma and diffuse large cell lymphoma cells were moderately sensible to CDC, and small lymphocytic lymphoma cells were almost all resistant. We propose that CDC is a determinant mechanism of rituximab-induced killing in vivo. Poor sensitivity to CDC in vitro might predict a poor clinical response, whereas high sensitivity to CDC would only indicate a likelihood of response to rituximab treatment.
Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity
Authors: Amrolia Persis J. , Reid Steven D. , Gao Liquan , Schultheis Beate , Dotti Gianpietro , Brenner Malcolm K. , Melo Junia V. , Goldman John M. , Stauss Hans J.
Published: January 2003

Recent advances have made haploidentical transplantation for leukemia feasible, but the rigorous T-cell depletion used contributes to the high relapse rates observed. We have attempted to improve the graft-versus-leukemia (GVL) effect by generating allorestricted cytotoxic T lymphocytes (CTLs) directed against human CD45. Such CTLs should recognize patient hematopoietic cells including leukemia, enhancing donor cell engraftment and improving the GVL effect, but they should not recognize host nonhematopoietic tissues or donor cells from the graft. Using the T2 binding assay, 4 CD45-derived peptides were found to bind HLA-A2 molecules. These peptides were used to generate cytotoxic T-cell lines from HLA-A2− donors by sequential stimulation with peptide-pulsed HLA-A2+ stimulators, and the lines obtained were screened for peptide-specific cytotoxicity. Using one of these peptides (P1218), it was possible to generate peptide-specific, allorestricted CTLs in 3 of 7 responders. P1218-specific CTL lines show potent cytotoxicity against hematopoietic cell lines coexpressing HLA-A2 and CD45 but not CD45 loss variants. Studies with stable transfectants of 293 cells demonstrated recognition by P1218-specific CTLs of endogenously expressed CD45. Likewise P1218-specific CTLs recognized peripheral blood mononuclear cells (PBMCs) from HLA-A2+ patients with chronic myeloid leukemia (CML) and leukemic blasts in HLA-A2+ patients with acute myeloid leukemia (AML), but they were unable to lyse HLA-A2+ fibroblasts or HLA-A2− normal PBMCs. Coculture of CD34+ PBMCs and bone marrow mononuclear cells (BMMCs) with P1218-specific CTL significantly inhibited colony-forming unit–granulocyte macrophage (CFU-GM) formation in HLA-A2+healthy controls and CML patients but resulted in no significant inhibition in HLA-A2− healthy controls. These studies demonstrate that P1218-specific cytotoxic T lymphocytes (CTLs) have potent activity against leukemic progenitors and suggest that adoptive immunotherapy with allorestricted CTLs directed against CD45 epitopes may be useful in restoring the GVL effect after HLA-A2–mismatched haploidentical transplantation. Further, because P1218-specific CTLs also recognize healthy HLA-A2+ progenitors, such CTLs could also contribute to host myeloablation and enhance donor cell engraftment.
A macrophage colony-stimulating factor receptor–green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse
Authors: Sasmono R. Tedjo , Oceandy Delvac , Pollard Jeffrey W. , Tong Wei , Pavli Paul , Wainwright Brandon J. , Ostrowski Michael C. , Himes S. Roy , Hume David A.
Published: January 2003

The c-fms gene encodes the receptor for macrophage colony-stimulating factor (CSF-1). The gene is expressed selectively in the macrophage and trophoblast cell lineages. Previous studies have indicated that sequences in intron 2 control transcript elongation in tissue-specific and regulated expression of c-fms. In humans, an alternative promoter was implicated in expression of the gene in trophoblasts. We show that in mice, c-fmstranscripts in trophoblasts initiate from multiple points within the 2-kilobase (kb) region flanking the first coding exon. A reporter gene construct containing 3.5 kb of 5′ flanking sequence and the downstream intron 2 directed expression of enhanced green fluorescent protein (EGFP) to both trophoblasts and macrophages. EGFP was detected in trophoblasts from the earliest stage of implantation examined at embryonic day 7.5. During embryonic development, EGFP highlighted the large numbers of c-fms–positive macrophages, including those that originate from the yolk sac. In adult mice, EGFP location was consistent with known F4/80-positive macrophage populations, including Langerhans cells of the skin, and permitted convenient sorting of isolated tissue macrophages from disaggregated tissue. Expression of EGFP in transgenic mice was dependent on intron 2 as no lines with detectable EGFP expression were obtained where either all of intron 2 or a conserved enhancer element FIRE (theFms intronic regulatory element) was removed. We have therefore defined the elements required to generate myeloid- and trophoblast-specific transgenes as well as a model system for the study of mononuclear phagocyte development and function.
Hemogenic and nonhemogenic endothelium can be distinguished by the activity of fetal liver kinase (Flk)–1promoter/enhancer during mouse embryogenesis
Authors: Hirai Hideyo , Ogawa Minetaro , Suzuki Norio , Yamamoto Masayuki , Breier Georg , Mazda Osam , Imanishi Jiro , Nishikawa Shin-Ichi
Published: January 2003

Accumulating evidence in various species has suggested that the origin of definitive hematopoiesis is associated with a special subset of endothelial cells (ECs) that maintain the potential to give rise to hematopoietic cells (HPCs). In this study, we demonstrated that a combination of 5′-flanking region and 3′ portion of the first intron of the Flk-1 gene (Flk-1 p/e) that has been implicated in endothelium-specific gene expression distinguishes prospectively the EC that has lost hemogenic activity. We assessed the activity of this Flk-1 p/e by embryonic stem (ES) cell differentiation culture and transgenic mice by using theGFP gene conjugated to this unit. The expression ofGFP differed from that of the endogenous Flk-1gene in that it is active in undifferentiated ES cells and inactive in Flk-1+ lateral mesoderm. Flk-1 p/e becomes active after generation of vascular endothelial (VE)–cadherin+ ECs. Emergence of GFP− ECs preceded that of GFP+ ECs, and, finally, most ECs expressed GFP both in vitro and in vivo. Cell sorting experiments demonstrated that only GFP− ECs could give rise to HPCs and preferentially expressed Runx1 and c-Myb genes that are required for the definitive hematopoiesis. Integration of both GFP+ and GFP− ECs was observed in the dorsal aorta, but cell clusters appeared associated only to GFP−ECs. These results indicate that activation of Flk-1 p/e is associated with a process that excludes HPC potential from the EC differentiation pathway and will be useful for investigating molecular mechanisms underlying the divergence of endothelial and hematopoietic lineages.
The zinc finger transcription factor ZBP-89 is a repressor of the human β2-integrin CD11b gene
Authors: Park Heiyoung , Shelley C. Simon , Arnaout M. Amin
Published: January 2003

Integrin CD11b is a differentiation marker of the myelomonocytic lineage and an important mediator of inflammation. Expression of theCD11b gene is transcriptionally induced as myeloid precursors differentiate into mature cells, then drops as monocytes further differentiate into macrophages. Previous studies have identified elements and factors involved in the transcriptional activation of the CD11b gene during myeloid differentiation, but no data exist regarding potential down-regulatory factors, especially in the later stages of differentiation. Using 2 copies of a GC-rich element (−141 to −110) in the CD11bpromoter, we probed a cDNA expression library for interacting proteins. Three clones were identified among 9.1 million screened, all encoding the DNA-binding domain of the zinc finger factor ZBP-89. Overexpression of ZBP-89 in the monocyte precursor cell line U937 reducedCD11b promoter-driven luciferase activity when U937 cells were induced to differentiate into monocytelike cells using phorbol esters. To identify the differentiation stage at which ZBP-89 repression of the CD11b gene is exerted, the protein level of ZBP-89 was correlated with that of CD11b mRNA in differentiating U937 as well as in normal human monocytes undergoing in vitro differentiation into macrophages. A clear inverse relationship was observed in the latter but not the former state, suggesting that ZBP-89 represses CD11b gene expression during the further differentiation of monocytes into macrophages.
Identification of a novel class of human adherent CD34− stem cells that give rise to SCID-repopulating cells
Authors: Kuçi Selim , Wessels Johannes T. , Bühring Hans-Jörg , Schilbach Karin , Schumm Michael , Seitz Gabriele , Löffler Jürgen , Bader Peter , Schlegel Paul G. , Niethammer Dietrich , Handgretinger Rupert
Published: January 2003

Here we describe the in vitro generation of a novel adherent cell fraction derived from highly enriched, mobilized CD133+ peripheral blood cells after their culture with Flt3/Flk2 ligand and interleukin-6 for 3 to 5 weeks. These cells lack markers of hematopoietic stem cells, endothelial cells, mesenchymal cells, dendritic cells, and stromal fibroblasts. However, all adherent cells expressed the adhesion molecules VE-cadherin, CD54, and CD44. They were also positive for CD164 and CD172a (signal regulatory protein-α) and for a stem cell antigen defined by the recently described antibody W7C5. Adherent cells can either spontaneously or upon stimulation with stem cell factor give rise to a transplantable, nonadherent CD133+CD34−stem cell subset. These cells do not generate in vitro hematopoietic colonies. However, their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice induced substantially higher long-term multilineage engraftment compared with that of freshly isolated CD34+ cells, suggesting that these cells are highly enriched in SCID-repopulating cells. In addition to cells of the myeloid lineage, nonadherent CD34− cells were able to give rise to human cells with B-, T-, and natural killer–cell phenotype. Hence, these cells possess a distinct in vivo differentiation potential compared with that of CD34+ stem cells and may therefore provide an alternative to CD34+ progenitor cells for transplantation.
Constitutive overexpression of IL-5 induces extramedullary hematopoiesis in the spleen
Authors: Khaldoyanidi Sophia , Sikora Lyudmila , Broide David H. , Rothenberg Marc E. , Sriramarao P.
Published: January 2003

The differentiation of eosinophils from hematopoietic precursors and their subsequent maturation, chemotaxis, and activation is primarily regulated by interleukin-5 (IL-5). To examine the effect of chronic IL-5 exposure on hematopoiesis, IL-5 transgenic (IL-5trg) mice and wild-type BALB/c (WT) mice were examined. In comparison to WT mice, a significant alteration in bone marrow hematopoiesis was observed in IL-5trg mice. Although the total number of myeloid progenitors in the bone marrow of IL-5trg mice was not significantly altered, the number of long-term culture-initiating cells (LTC-ICs) was 1.5-fold lower than that observed in WT mice. Furthermore, IL-5trg mice failed to demonstrate hematopoietic activity in long-term bone marrow cultures, which correlated with a significant decrease in the number of bone marrow mesenchymal/stromal progenitor (MSP) cells in these mice. In comparison to WT mice, a 10-fold decrease was observed in the number of fibroblast colony-forming units (CFU-Fs) in IL-5trg bone marrow. Hematopoietic activity of IL-5trg bone marrow cells was rescued by cultivation on preestablished layers of bone marrow-derived stromal cells. However, in contrast to bone marrow, increased hematopoietic activity was observed in the spleen and peripheral blood of IL-5trg mice. Likewise, the numbers of LTC-ICs and granulocyte-macrophage, macrophage, eosinophil, B-lymphocyte progenitors in the peripheral blood and spleen of IL-5trg mice were approximately 20-fold higher than in WT mice. A significant increase in CFU-F numbers was also observed in the spleens of IL-5trg mice compared with WT mice. Overall, our results suggest that constitutive overexpression of IL-5 can potentially induce colonization of spleen with MSP cells, which provides the necessary microenvironment for establishment of hematopoiesis in extramedullary sites.
Involvement of p38 mitogen–activated protein kinase in different stages of thymocyte development
Authors: Hsu Shu-Ching , Wu Chia-Cheng , Han Jiahuai , Lai Ming-Zong
Published: January 2003

Positive selection of thymocytes during T-cell development is mediated by T-cell receptor (TCR)–activated signals. For different mitogen-activated protein kinases (MAPKs) activated by TCR complex, a selective involvement of extracellular signal–regulated kinase, but not p38 MAPK, in positive selection has been suggested. Using transgenic mice with dominant-negative mutation of both MAP kinase kinase 3 (MMK3) and MKK6, we obtained mice with different extents of inhibition of p38 MAPK activation. Partial inhibition of p38 MAPK impaired CD4−CD8− thymocyte development and T-cell proliferation, but not positive selection. Interference with thymocyte positive selection was observed in mice with effective suppression of p38 MAPK. Our results suggest that, in addition to early thymocyte development, p38 is involved in positive selection.
Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia
Authors: Rezvany Mohammad-Reza , Jeddi-Tehrani Mahmood , Wigzell Hans , Österborg Anders , Mellstedt Håkan
Published: January 2003

T-cell receptor–B-variable (TCR-BV) gene usage and the CDR3 size distribution pattern were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) in patients with B-cell chronic lymphocytic leukemia (B-CLL) to assess the T-cell repertoire. The use of TCR-BV families in CD4 and CD8 T cells stimulated with autologous activated leukemic cells was compared with that of freshly obtained blood T cells. Overexpression of individual TCR-BV families was found in freshly isolated CD4 and CD8 T cells. Polyclonal, oligoclonal, and monoclonal TCR-CDR3 patterns were seen within such overexpressed native CD4 and CD8 TCR-BV families. In nonoverexpressed TCR-BV families, monoclonal and oligoclonal populations were noted only within the CD8 subset. After in vitro stimulation of T cells with autologous leukemic B cells, analyses of the CDR3 length patterns showed that in expanded TCR-BV populations, polyclonal patterns frequently shifted toward a monoclonal/oligoclonal profile, whereas largely monoclonal patterns in native overexpressed TCR-BV subsets remained monoclonal. Seventy-five percent of CD8 expansions found in freshly obtained CD8 T cells further expanded on in vitro stimulation with autologous leukemic B cells. This suggests a memory status of such cells. In contrast, the unusually high frequency of CD4 T-cell expansions found in freshly isolated peripheral blood cells did not correlate positively to in vitro stimulation as only 1 of 9 expansions continued to expand. Our data suggest that leukemia cell–specific memory CD4 and CD8 T cells are present in vivo of patients with CLL and that several leukemia cell–associated antigens/epitopes are recognized by the patients' immune system, indicating that whole leukemia cells might be of preference for vaccine development.
Laminin isoform–specific promotion of adhesion and migration of human bone marrow progenitor cells
Authors: Gu Yu-Chen , Kortesmaa Jarkko , Tryggvason Karl , Persson Jenny , Ekblom Peter , Jacobsen Sten-Eirik , Ekblom Marja
Published: January 2003

Laminins are αβγ heterotrimeric extracellular proteins that regulate cellular functions by adhesion to integrin and nonintegrin receptors. Laminins containing α4 and α5 chains are expressed in bone marrow, but their interactions with hematopoietic progenitors are unknown. We studied human bone marrow cell adhesion to laminin-10/11 (α5β1γ1/α5β2γ1), laminin-8 (α4β1γ1), laminin-1 (α1β1γ1), and fibronectin. About 35% to 40% of CD34+ and CD34+CD38− stem and progenitor cells adhered to laminin-10/11, and 45% to 50% adhered to fibronectin, whereas they adhered less to laminin-8 and laminin-1. Adhesion of CD34+CD38− cells to laminin-10/11 was maximal without integrin activation, whereas adhesion to other proteins was dependent on protein kinase C activation by 12-tetradecanoyl phorbol-13-acetate (TPA). Fluorescence-activated cell-sorting (FACS) analysis showed expression of integrin α6 chain on most CD34+ and CD34+CD38−cells. Integrin α6 and β1 chains were involved in binding of both cell fractions to laminin-10/11 and laminin-8. Laminin-10/11 was highly adhesive to lineage-committed myelomonocytic and erythroid progenitor cells and most lymphoid and myeloid cell lines studied, whereas laminin-8 was less adhesive. In functional assays, both laminin-8 and laminin-10/11 facilitated stromal-derived factor-1α (SDF-1α)–stimulated transmigration of CD34+ cells, by an integrin α6 receptor–mediated mechanism. In conclusion, we demonstrate laminin isoform–specific adhesive interactions with human bone marrow stem, progenitor, and more differentiated cells. The cell-adhesive laminins affected migration of hematopoietic progenitors, suggesting a physiologic role for laminins during hematopoiesis.