bluuebunny/crossref_metadata_2025 huggingface dataset:
A Bayesian Framework for Sensory Adaptation
Authors: Grzywacz Norberto M. , Balboa Rosario M.
Published: July 2002

Adaptation allows biological sensory systems to adjust to variations in the environment and thus to deal better with them. In this article, we propose a general framework of sensory adaptation. The underlying principle of this framework is the setting of internal parameters of the system such that certain prespecified tasks can be performed optimally. Because sensorial inputs vary probabilistically with time and biological mechanisms have noise, the tasks could be performed incorrectly. We postulate that the goal of adaptation is to minimize the number of task errors. This minimization requires prior knowledge of the environment and of the limitations of the mechanisms processing the information. Because these processes are probabilistic, we formulate the minimization with a Bayesian approach. Application of this Bayesian framework to the retina is successful in accounting for a host of experimental findings.
A Unified Analysis of Value-Function-Based Reinforcement-Learning Algorithms
Authors: Szepesvári Csaba , Littman Michael L.
Published: July 2002

Reinforcement learning is the problem of generating optimal behavior in a sequential decision-making environment given the opportunity of interacting with it. Many algorithms for solving reinforcement-learning problems work by computing improved estimates of the optimal value function. We extend prior analyses of reinforcement-learning algorithms and present a powerful new theorem that can provide a unified analysis of such value-function-based reinforcement-learning algorithms. The usefulness of the theorem lies in how it allows the convergence of a complex asynchronous reinforcement-learning algorithm to be proved by verifying that a simpler synchronous algorithm converges. We illustrate the application of the theorem by analyzing the convergence of Q-learning, model-based reinforcement learning, Q-learning with multistate updates, Q-learning for Markov games, and risk-sensitive reinforcement learning.
A Real-Time Algorithm for Accurate Collision Detection for Deformable Polyhedral Objects
Authors: Kitamura Yoshifumi , Smith Andrew , Takemura Haruo , Kishino Fumio
Published: July 2002

We propose an accurate collision detection algorithm for use in virtual reality applications. The algorithm works for three-dimensional graphical environments where multiple objects, represented as polyhedra (boundary representation), are undergoing arbitrary motion (translation and rotation). The algorithm can be used directly for both convex and concave objects and objects can be deformed (nonrigid) during motion. The algorithm works efficiently by first reducing the number of face pairs that need to be checked accurately for interference, by first localizing possible collision regions using bounding box and spatial subdivision techniques. Face pairs that remain after this pruning stage are then accurately checked for interference. The algorithm is efficient, simple to implement, and does not require any memory-intensive auxiliary data structures to be precomputed and updated. The performance of the proposed algorithm is compared directly against other existing algorithms, e.g., the separating plane algorithm, octree update method, and distance-based method. Results are given to show the efficiency of the proposed method in a general environment.
Self-Adaptation in Evolving Systems
Authors: Stephens C. R. , Olmedo I. García , Vargas J. Mora , Waelbroeck H.
Published: July 2002

A theoretical and experimental analysis is made of the effects of self-adaptation in a simple evolving system. Specifically, we consider the effects of coding the mutation and crossover probabilities of a genetic algorithm evolving in certain model fitness landscapes. The resultant genotypephenotype mapping is degenerate in fitness space, there being no direct selective advantage for one probability versus another. Thus there is a “symmetry” between various genotypes that all correspond to the same phenotype. We show that the action of mutation and crossover lifts this degeneracy, that is, the genetic operators induce a breaking of the genotype-phenotype symmetry, thus leading to a preference for those genotypes that propagate most successfully into future generations. We demonstrate that this induced symmetry breaking allows the system to self-adapt in a time-dependent environment.
Visualizing Evolutionary Activity of Genotypes
Authors: Bedau Mark A. , Brown C. Titus
Published: July 2002

We introduce a method for visualizing evolutionary activity of genotypes. Following a proposal of Bedau and Packard [11], we define a genotype's evolutionary activity in terms of the history of its concentration in the evolving population. To visualize this evolutionary activity we graph the distribution of evolutionary activity in the population of genotypes as a function of time. Adaptively significant genotypes trace a salient line or “wave” in these graphs. The quality of these waves indicates a variety of evolutionary phenomena, such as competitive exclusion, neutral variation, and random genetic drift. We apply this method in an evolutionary model of self-replicating assembly language programs competing for room in a two-dimensional space. Comparison with fitness graphs and with a nonadaptive analogue of this model shows how this method highlights adaptively significant events.
The Oil Mallee Project: A Multifaceted Industrial Ecology Case Study
Authors: Barton Allan
Published: July 2002

The planting on degraded agricultural lands of eucalypts for leaf oil provides a commercial incentive for restoring original vegetation; a sustainable method of controlling groundwater and salinity; a product that is an environmentally benign substitute for a widely used solvent damaging to the ozone layer; and a mechanism for reducing atmospheric carbon dioxide levels. With integrated tree crop systems and improved harvesting and processing technologies, the Western Australian wheatbelt could produce large volumes of high‐cineole eucalyptus oil from mallee eucalypts. With new industrial markets, a scale of planting could be achieved that would result in substantial land rehabilitation benefits. Industrial solvent markets are large and currently in transition following the recent withdrawal of 1,1,1‐trichloroethane as a result of international measures to control ozone depletion. There is a strong preference in these markets for “natural” replacement products. Although large‐scale penetration of these markets would need prices about half those prevailing in traditional eucalyptus oil markets, this goal should be achievable with the potential for economies of scale, genetic advances, and improved harvesting and processing technologies.
THE ORIGIN OF THE SCAPEGOAT RITUAL
Authors: Carmichael Calum
Published: July 2002

This paper argues, contrary to the dominant view, that the ritual of the scapegoat in Leviticus xvi is a purely native, Israelite invention, not a modification of pre-Israelite, Near Eastern rites. The key to its construction is the procedure by which the biblical lawgiver examined his nation's traditions, singled out the first time a particular issue arose, and presented a law ostensibly the product of Moses' judgment. In the case of the scapegoat ritual, the issue he focussed on is the occasion when Joseph's brothers seek forgiveness for their offence against Joseph, thereby transferring to the beast their own wrongdoing. The thesis revives a view found as early as the Book of Jubilees and which turns up again in Maimonides that the Day of Atonement was first instituted to expiate the brothers' offence against Joseph.
Characteristics and origin of sepiolite (Meerschaum) from Central Somalia
Authors: Singer A. , Stahr K. , Zarei M.
Published: July 2002

Nearly pure sepiolite clay crops out in a playa-like depression near El Bur, Central Plateau region of Somalia. The deposit is associated with the Lower to Mid-Eocene Taleh Formation that includes, besides limestone, dolomite and gypsiferous marls, extensive anhydrite and various evaporites, primarily gypsum. The material was examined by XRD, DTA, IR and EM. The XRD and DTA analyses indicated that from 40 cm down to a depth of 300 cm, the material consists of well crystallized sepiolite, accompanied in some layers by minor calcite and traces of quartz and halite. The chemical composition, determined by XRF, indicated a low-Fe mineral, with the formula: (Si11.888Al0.l12)(Mg7.313Al0.154Fe0.084)O30(OH2)4(OH2)4.x8H2O.

The fibres, arranged in the form of interwoven mats, are straight and have lengths varying between 2-6 µm and widths of 20-40 nm. Commonly, they are aggregated into units of two parallel-lying fibres, with a random orientation against each other, creating a dense network of pores. The high viscosity and external surface area (306-346 m2g-1) of the material, compared to those of the Spanish Vallecas sepiolite, suggest the high industrial suitability of this clay. The extent of the deposit is not known. Lithology and geomorphology indicate a lacustrine, closed basin evaporative environment of formation for this deposit. In contrast to the palaeolacustrine environments of formation of Spanish and Turkish sepiolite deposits, the E1 Bur sepiolite apparently is more recent.
Grain-size distribution of Italian raw materials for building clay products: a reappraisal of the Winkler diagram
Authors: Dondi M. , Fabbri B. , Guarini G.
Published: July 2002

The grain size of raw materials influences their behaviour during the technological process and affects many properties of building clay products. Over the last few years, brickworks have been technologically updated and grain size requirements have been modified to ensure good behaviour during shaping and drying. Therefore, the reference schemes used to assess the suitability of clays, such as the classic Winkler diagram, should be updated.

For this purpose, the grain-size distribution of 350 clays currently used in ~240 Italian plants was determined by X-ray monitoring of gravity sedimentation. Raw materials are basically represented by silty clays and clayey silts, while bodies present a narrower grain-size range. With reference to the Winkler diagram, most of the Italian bodies fall within the field of ‘thin-walled hollow bricks’, with no significant differentiation among the various product types.

In order to improve the grain-size characterization of bodies, a new classification scheme for Italian raw materials is proposed, based on three ranges: >10 µm, 2-10 µm and <2 µm, respectively. It allows distinction of specific grain-size features of bodies for (a) facing bricks; (b) roofing tiles; and (c) lightweight blocks, paving bricks and hollow slabs.
Crystal chemistry of basic lead carbonates. II. Crystal structure of synthetic ‘plumbonacrite’
Authors: Krivovichev S. V. , Burns P. C.
Published: July 2002

The crystal structure of synthetic ‘plumbonacrite’, Pb5O(OH)2(CO3)3, hexagonal, P63cm, a = 9.0921(7), c = 24.923(3)Å, V = 1784.3(3)Å3, Z = 6, has been solved by direct methods and refined to R = 0.049. There are six symmetrically independent Pb2+ positions in the structure, the coordination polyhedra of which are strongly distorted due to the effect of s2 lone-electron pairs on the Pb2+ cations. The Pb(6) position is disordered with a Pb–Pb distance of 1.24 Å . The structure of ‘plumbonacrite’ is built from complex Pb–O layers parallel to the (001) plane similar to those observed in polymorphs of Pb4(OH)2(SO4)(CO3)2. The structure of these layers can be described in terms of Pb–O,OH motifs and CO3 groups. The smallest structural subunit is the oxocentred [OPb4] tetrahedron that shares three of its Pb-Pb edges with three [(OH)Pb3] distorted triangles to form [O(OH)3Pb7] clusters. These clusters are surrounded by CO3 groups, forming more complex clusters. Due to the disorder in the Pb(6) site, the clusters comprising this site are linked with each other via OH(10) groups to give continuous sheets of Pb–O,OH bonds which are parallel to the (001) plane. The [O(OH)3Pb7] clusters in ‘plumbonacrite’ may be important in more complex Pb carbonate oxo/hydroxo complexes that may exist in aqueous environments.
Exotic aluminium phosphates, natromontebrasite, brazilianite, goyazite, gorceixite and crandallite from rare-element pegmatites in Namibia
Authors: Baldwin J. R. , Hill P. G. , von Knorring O. , Oliver G. J. H.
Published: July 2002

Replacement phenomena in amblygonite–montebrasite in rare-element pegmatites from the Karibib-Usakos area, Namibia, have been investigated using the electron microprobe. The first African occurrence and analysis of the very rare mineral natromontebrasite NaAl(PO4)(OH,F) is reported from the Daheim pegmatite. In the Okatjimukuju pegmatite, montebrasite has been replaced by a number of phases including crandallite CaAl3(PO4)2(OH)5·H2O and brazilianite NaAl3(PO4)2(OH)4. In one example, montebrasite has been almost completely replaced by brazilianite which has also been found to contain not only crandallite but also its solid solution analogues: goyazite SrAl3(PO4)2(OH)5·H2O and gorceixite BaAl3(PO4)2(PO3OH)(OH)6. Apatite is common at the contacts with montebrasite and associated minerals and texturally is intimately intergrown with crandallite, goyazite and gorceixite at Okatjimukuju. The occurrence of these minerals offers insight into the chemistry of post-magmatic fluids in these pegmatites.
Refinement of the crystal structure of a synthetic non-stoichiometric Rb-feldspar
Authors: Kyono A. , Kimata M.
Published: July 2002

The crystal structure of hydrothermally synthesized Rb-feldspar (monoclinic, space group C2/m, a= 8.839(2)Å, b= 13.035(2)Å, c= 7.175(2)Å, β = 116.11(1)8, V= 742.3(3)Å3, Z= 4) has been refined to a final R of 0.0574 for 692 independent X-ray reflections. Microprobe analyses of the Rb-feldspar suggest deviation from stoichiometry, with excess Si and Al, resulting in a unit formula of Rb0.811□0.127Al1.059Si3.003O8. Infrared (IR) spectra indicate the structural occupancy of large H2O content, which implies that the □Si4O8 substitution favours the structural incorporation of the H2O molecule at the M-site. The mean T–O distances are 1.632 Å for T1 and 1.645 Å for T2, revealing highly disordered (Al,Si) distribution with Al/Si = 0.245/0.755 (T1 site) and 0.255/0.745 (T2 site).

There are two geochemical implications from this refinement: (1) identification of both rubicline triclinic with (Al,Si) ordered distribution and synthetic monoclinic RbAlSi3O8 with (Al,Si) disordered distribution implies that Rb cannot be one of factors disrupting the (Al,Si) ordered and disordered distributions in feldspars; and (2) natural and synthetic feldspars capable of accommodating the large cations tend to incorporate □Si4O8, excess Al and H2O components in their crystal structures.
Numerous growth factors, cytokines, and chemokines are secreted by human CD34+ cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner
Authors: Majka Marcin , Janowska-Wieczorek Anna , Ratajczak Janina , Ehrenman Karen , Pietrzkowski Zbigniew , Kowalska M. Anna , Gewirtz Alan M. , Emerson Stephen G. , Ratajczak Mariusz Z.
Published: July 2002

The aim of this study was to explore further the hypothesis that early stages of normal human hematopoiesis might be coregulated by autocrine/paracrine regulatory loops and by cross-talk among early hematopoietic cells. Highly purified normal human CD34+cells and ex vivo expanded early colony-forming unit–granulocyte-macrophage (CFU-GM)–derived, burst forming unit–erythroid (BFU-E)–derived, and CFU–megakaryocyte (CFU-Meg)–derived cells were phenotyped for messenger RNA expression and protein secretion of various growth factors, cytokines, and chemokines to determine the biological significance of this secretion. Transcripts were found for numerous growth factors (kit ligand [KL], FLT3 ligand, fibroblast growth factor–2 [FGF-2], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], insulinlike growth factor–1 [IGF-1], and thrombopoietin [TPO]); cytokines (tumor necrosis factor–α, Fas ligand, interferon α, interleukin 1 [IL-1], and IL-16); and chemokines (macrophage inflammatory protein–1α [MIP-1α], MIP-1β, regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein–3 [MCP-3], MCP-4, IL-8, interferon-inducible protein–10, macrophage-derived chemokine [MDC], and platelet factor–4 [PF-4]) to be expressed by CD34+ cells. More importantly, the regulatory proteins VEGF, HGF, FGF-2, KL, FLT3 ligand, TPO, IL-16, IGF-1, transforming growth factor–β1 (TGF-β1), TGF-β2, RANTES, MIP-1α, MIP-1β, IL-8, and PF-4 were identified in media conditioned by these cells. Moreover, media conditioned by CD34+ cells were found to inhibit apoptosis and slightly stimulate the proliferation of other freshly isolated CD34+ cells; chemo-attract CFU-GM– and CFU-Meg–derived cells as well as other CD34+ cells; and, finally, stimulate the proliferation of human endothelial cells. It was also demonstrated that these various hematopoietic growth factors, cytokines, and chemokines are expressed and secreted by CFU-GM–, CFU-Meg–, and BFU-E–derived cells. It is concluded that normal human CD34+ cells and hematopoietic precursors secrete numerous regulatory molecules that form the basis of intercellular cross-talk networks and regulate in an autocrine and/or a paracrine manner the various stages of normal human hematopoiesis.
Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1
Authors: Riewald Matthias , Kravchenko Vladimir V. , Petrovan Ramona J. , O'Brien Peter J. , Brass Lawrence F. , Ulevitch Richard J. , Ruf Wolfram
Published: July 2002

Cell signaling by coagulation factor Xa (Xa) contributes to pro-inflammatory responses in vivo. This study characterizes the signaling mechanism of Xa in a HeLa cell line that expresses protease-activated receptor 1 (PAR-1) but not PAR-2, -3, or -4. Xa induced NF-κB in HeLa cells efficiently but with delayed kinetics compared to thrombin. This delay caused no difference in gene expression patterns, as determined by high-density microarray analysis. Both proteases prominently induced the angiogenesis-promoting geneCyr61 and connective tissue growth factor. Inhibition of PAR-1 cleavage abolished MAP kinase phosphorylation and gene induction by Xa, demonstrating that Xa signals through PAR-1 and not through a novel member of the PAR family. Activation of cell surface prothrombin with the snake venom enzyme Ecarin also produced PAR-1–dependent signaling. However, though the response to Ecarin was completely blocked by the thrombin inhibitor hirudin, the response to Xa was not. This suggests that the Xa response is not mediated by locally generated thrombin. The concentration dependence of Xa for PAR-1 activation is consistent with previously characterized Xa-mediated PAR-2 signaling, suggesting that local concentration of Xa on the cell surface, rather than sequence-specific recognition of the PAR scissile bond, determines receptor cleavage. This study demonstrates that PAR-1 cleavage by Xa can elicit the same cellular response as thrombin, but mechanistic differences in receptor recognition may be crucial for specific roles for Xa in signaling during spatial or temporal separation from thrombin generation.
Selective inhibition of interleukin-4 gene expression in human T cells by aspirin
Authors: Cianferoni Antonella , Schroeder John T. , Kim Jean , Schmidt John W. , Lichtenstein Lawrence M. , Georas Steve N. , Casolaro Vincenzo
Published: July 2002

Previous studies indicated that aspirin (acetylsalicylic acid [ASA]) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells. This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin (IL)-4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells. In contrast, ASA did not affect IL-13, interferon-γ, and IL-2 expression. ASA inhibited IL-4, but not IL-2, promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells. The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells, whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity. The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor (NF)–κB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of, but not overlapping, the NF of activated T cells– and NF-κB–binding P1 element. It is concluded that anti-inflammatory salicylates, by means of a previously unrecognized mechanism of action, can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4, a critical effector of these responses, in CD4+ T cells.
CD9 and megakaryocyte differentiation
Authors: Clay Denis , Rubinstein Eric , Mishal Zohair , Anjo Aurora , Prenant Michel , Jasmin Claude , Boucheix Claude , Bousse-Kerdilès Marie-Caroline Le
Published: July 2002

It is shown that the tetraspanin CD9 has a complex pattern of distribution in hematopoietic cells and is heterogeneously expressed on human bone marrow CD34+ cells. CD34highCD38lowThy1+ primitive progenitors are contained in the population with intermediate CD9 expression, thus suggesting that CD9 expression may precede CD38 appearance. Cell sorting shows that colony-forming unit (CFU)-GEMM and CFU-GM are present in high proportions in this fraction and in the fraction with the lowest CD9 expression. Cells with the highest level of CD9 are committed to the B-lymphoid or megakaryocytic (MK) lineages, as shown by the co-expression of either CD19 or CD41/GPIIb and by their strong potential to give rise to CFU-MK. In liquid cultures, CD9highCD41neg cells give rise to cells with high CD41 expression as early as 2 days, and this was delayed by at least 3 to 4 days for the CD9mid cells; few CD41high cells could be detected in the CD9lowcell culture, even after 6 days. Antibody ligation of cell surface CD9 increased the number of human CFU-MK progenitors and reduced the production of CD41+ megakaryocytic cells in liquid culture. This was associated with a decreased expression of MK differentiation antigens and with an alteration of the membrane structure of MK cells. Altogether these data show a precise regulation of CD9 during hematopoiesis and suggest a role for this molecule in megakaryocytic differentiation, possibly by participation in membrane remodeling.
Glycophorin A dimerization and band 3 interaction during erythroid membrane biogenesis: in vivo studies in human glycophorin A transgenic mice
Authors: Auffray Isabelle , Marfatia Shirin , de Jong Kitty , Lee Gloria , Huang Cheng-Han , Paszty Chris , Tanner Michael J. A. , Mohandas Narla , Chasis Joel Anne
Published: July 2002

Band 3 and glycophorin A (GPA) are the 2 most abundant integral proteins in the human erythrocyte membrane. Earlier studies suggested that the 2 proteins may associate not only in the mature erythrocyte membrane, but also during their posttranslational processing and intracellular trafficking. The purpose of this study was to directly examine the GPA–band 3 interaction in vivo and determine the nature of this association during erythroid membrane biogenesis. Transgenic mice were generated expressing the human glycophorin A gene and were used to examine how the induction of human GPA expression affected the levels of murine GPA and band 3 expression in the red cell membrane. Murine GPA expression was reduced in erythrocytes expressing human GPA, whereas the level of band 3 expression remained constant, implying a tight coupling of band 3 and GPA expression in the membrane of mature red cells. In vivo GPA dimerization was not modulated solely by the GPA transmembrane motif, but the distance between this motif and the basic residues on the cytoplasmic side of the transmembrane domain may also be important. In addition, GPA monomers with varying degrees of glycosylation dimerized, providing clear evidence that carbohydrate structures on the extracellular domain do not affect dimerization. The association between the multiple transmembrane-spanning protein, band 3, and the single transmembrane-spanning sialoglycoprotein, GPA, may serve as a model for interactions of other multi-pass and single-pass polypeptides during membrane biogenesis.
Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia
Authors: Wang Changqing , Chiarelli Laurent R. , Bianchi Paola , Abraham Donald J. , Galizzi Alessandro , Mattevi Andrea , Zanella Alberto , Valentini Giovanna
Published: July 2002

Human erythrocyte pyruvate kinase plays an important role in erythrocyte metabolism. Mutation on the gene results in pyruvate kinase deficiency and is an important cause of hereditary nonspherocytic hemolytic anemia. Because of difficulties in isolating the mutant enzymes from patients, these mutations have not been fully studied. In this study, a complementary DNA (cDNA) encoding the human erythrocyte pyruvate kinase was generated. The cDNA was cloned into several expression vectors, and the protein was expressed and purified. The tetrameric protein exhibited properties characteristic of authentic human erythrocyte pyruvate kinase, including response to substrate, phosphoenolpyruvate, activation by fructose 1,6-bisphosphate, and inhibition by adenosine triphosphate (ATP). The N-terminal segment of the protein was highly susceptible to proteolysis, but only 2 of the 4 subunits were cleaved and lacked 47 N-terminal amino acid residues. A mutant protein, R510Q, which is the most frequently occurring mutation among Northern European population, was also generated and purified. The mutant protein retained its binding capacity to and could be activated by fructose 1,6-bisphosphate and showed similar kinetics toward phosphoenolpyruvate and adenosine diphosphate as for the wild-type enzyme. Conversely, the mutant protein has a dramatically decreased stability toward heat and is more susceptible to ATP inhibition. The enzyme instability decreases the enzyme level in the cell, accounting for the clinically observed “pyruvate kinase deficiency” of patients who are homozygous for this mutation. This study provides the first detailed functional characterization of human erythrocyte pyruvate kinase. These findings will allow the establishment of a fine correlation between molecular abnormalities and the clinical expression of the disease.
Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea–hypopnea syndrome
Authors: Imagawa Shigehiko , Yamaguchi Yuji , Higuchi Masato , Neichi Tomohiro , Hasegawa Yuichi , Mukai Harumi Y. , Suzuki Norio , Yamamoto Masayuki , Nagasawa Toshiro
Published: July 2002

To better understand how humans adapt to hypoxia, the levels of hemoglobin (Hb), serum erythropoietin (Epo), and vascular endothelial growth factor (VEGF) were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found. The induction in patients with severe sleep apnea was greater than that reported in other types of hypoxia.
Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice
Authors: Cetkovic-Cvrlje Marina , Roers Bertram A. , Waurzyniak Barbara , Liu Xing-Ping , Uckun Fatih M.
Published: July 2002

To prevent the development of acute graft-versus-host disease (GVHD) in lethally irradiated C57BL/6 (H-2b) recipient mice transplanted with bone marrow–splenocyte grafts from major histocompatibility complex (MHC) disparate BALB/c mice (H-2d), recipient mice were treated with the rationally designed JAK3 inhibitor WHI-P131 [4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (20 mg/kg, 3 times a day [tid]) daily from the day of bone marrow transplantation (BMT) until the end of the 85-day observation period. Total body irradiation (TBI)-conditioned, vehicle-treated control C57BL/6 mice (n = 38) receiving bone marrow–splenocyte grafts from BALB/c mice survived acute TBI toxicity, but they all developed histologically confirmed severe multi-organ GVHD and died after a median survival time of 37 days. WHI-P131 treatment (20 mg/kg intraperitoneally, tid) prolonged the median survival time of the BMT recipients to 56 days. The probability of survival at 2 months after BMT was 11% ± 5% for vehicle-treated control mice (n = 38) and 41% ± 9% for mice treated with WHI-P131 (n = 32) (P < .0001). Notably, the combination regimen WHI-P131 plus the standard anti-GVHD drug methotrexate (MTX) (10 mg/m2 per day) was more effective than WHI-P131 or MTX alone. More than half the C57BL/6 recipients receiving this most effective GVHD prophylaxis remained alive and healthy throughout the 85-day observation period, with a cumulative survival probability of 70% ± 10%. Taken together, these results indicate that targeting JAK3 in alloreactive donor lymphocytes with a chemical inhibitor such as WHI-P131 may attenuate the severity of GVHD after BMT.
CD8+ T cells are an in vivo reservoir for human T-cell lymphotropic virus type I
Authors: Nagai Masahiro , Brennan Meghan B. , Sakai Jill A. , Mora Carlos A. , Jacobson Steven
Published: July 2002

It is thought that human T-cell lymphotropic virus type I (HTLV-I) preferentially infects CD4+ T cells in vivo. However, observations of high HTLV-I proviral load in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis suggest that HTLV-I may infect other cell types in addition to CD4+ T cells. To identify in vivo T-cell tropisms of HTLV-I, real-time quantitative polymerase chain reaction (PCR) and intracellular protein staining were used. A high amount of HTLV-I proviral DNA was detected from purified CD8+ T cells by quantitative PCR (between 1.64 and 62.83 copies of HTLV-I provirus per 100 isolated CD8+ T cells). CD8+ T cells expressed HTLV-I–related antigens (HTLV-I Tax and p19 protein) after a short time in cultivation. These results demonstrate that CD8+ T cells are also infected with HTLV-I and express HTLV-I antigens at levels that are comparable to HTLV-I–infected CD4+ cells. Therefore, CD8+ cells are an additional viral reservoir in vivo for HTLV-I and may contribute to the pathogenesis of HTLV-I–mediated disorders.
Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells
Authors: Puig-Kröger Amaya , Relloso Miguel , Fernández-Capetillo Oskar , Zubiaga Ana , Silva Augusto , Bernabéu Carmelo , Corbı́ Angel L.
Published: July 2002

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor α [TNF-α] and interleukin-1β [IL-1β]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1–extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-α– and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor–mediated endocytic activity; nuclear factor-κB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-α. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.
A 385 insertion in the hypervariable region 1 of hepatitis C virus E2 envelope protein is found in some patients with mixed cryoglobulinemia type 2
Authors: Gerotto Martina , Dal Pero Francesca , Loffreda Stefano , Bianchi Francesco B. , Alberti Alfredo , Lenzi Marco
Published: July 2002

Chronic hepatitis C virus (HCV) infection has been associated with development of mixed cryoglobulinemia type 2 (MC2), a lymphoproliferative disorder characterized by B cell monoclonal expansion and immunoglobulin M/k cryoprecipitable immunoglobulin production. A short sequence (codons 384-410) of the HCV E2 protein, which has the potential to promote B cell proliferation, was investigated in 21 patients with HCV-related MC2 and in a control group of 20 HCV carriers without MC2. In 6 of the 21 (29%) patients with MC2, all the clones isolated from plasma, peripheral blood mononuclear cells, and liver showed sequence length variation compared with the hypervariable region 1 (HVR1) consensus sequence; 5 patients had an insertion at codon 385, and 1 patient had a deletion at codon 384. Inserted residues at position 385 were different within and between patients. No such mutations were observed in any of the HVR1 clones from control patients without MC2, and the difference between the 2 groups was statistically significant (P = .02). Analysis of 1345 HVR1 sequences obtained from GenBank strongly supported the conclusion that the observed insertions and deletion represent a rare event in HCV-infected patients, suggesting that they are significantly associated with MC2. The physical and chemical profiles of the 385 inserted residues detected in the MC2 patients were consistent with the possibility that these mutations, which occurred in a region containing immunodominant epitopes for neutralizing antibodies and binding sites for B lymphocytes, may be selected by functional constraints for interaction with host cells.
Modulation of Gardos channel activity by cytokines in sickle erythrocytes
Authors: Rivera Alicia , Jarolim Petr , Brugnara Carlo
Published: July 2002

It has recently been shown that the Gardos channel activity of mouse erythrocytes can be modified by endothelins, suggesting a functional linkage between endothelin receptors and the Gardos channel. Using 86Rubidium (86Rb) influx, effects were estimated of proinflammatory molecules such as platelet activator factor (PAF), endothelin-1 (ET-1), interleukin-10 (IL-10), and regulated on activation normal T cells expressed and secreted (RANTES) on the Gardos channel activity in human normal and sickle red cells. It was found that PAF (EC50: 15 ± 7 nM), RANTES (EC50, 9 ± 6 ng/mL [1.2 ± 0.8 nM]), IL-10 (EC50, 11 ± 8 ng/mL [204 ± 148 nM]), and ET-1 (EC50, 123 ± 34 nM) induce a significant increase in Gardos channel activity—between 28% and 84%—over the control. In addition, these agents modify the Gardos channel affinity for internal Ca++ (K0.5) by 2- to 6-fold. Biochemical evidence is provided for the presence of ET receptor subtype B in sickle and normal red cells. Furthermore, it was found that ET-1, PAF, RANTES, and IL-10 induce a significant increase in red cell density (P < .05). These data suggest that activation of the Gardos channel is functionally coupled to receptor motifs such as C-X-C (PAF), C-C (RANTES), and ET receptor subtype B. Thus, cell volume regulation or erythrocyte hydration states might be altered by activation of the Gardos channel by cytokines in vivo. The role of these mediators in promoting sickle cell dehydration in vivo is under investigation.
Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait
Authors: Kang Elizabeth M. , Areman Ellen M. , David-Ocampo Virginia , Fitzhugh Courtney , Link Mary E. , Read Elizabeth J. , Leitman Susan F. , Rodgers Griffin P. , Tisdale John F.
Published: July 2002

Mobilized peripheral blood is increasingly used as the source of hematopoietic stem cells for allogeneic transplantation, currently the only curative approach for sickle cell anemia. However, the safety and feasibility of stem cell mobilization in individuals with sickle cell trait (SCT) has not been documented. This study is a prospective controlled trial to evaluate the safety and feasibility of peripheral blood stem cell (PBSC) mobilization in 8 SCT subjects and 8 control subjects matched for age and race. Mobilization with filgrastim 10 μg/kg subcutaneous daily for 5 days was followed by 12-L apheresis on the fifth day. Filgrastim administration was accompanied by similar symptoms in all subjects; no untoward adverse events occurred in either group, including sickle cell crises. CD34+ cell mobilization response was not significantly different between SCT and control subjects. Median CD34+ cell content was also similar in PBSCs collected from SCT versus control subjects, 6.8 versus 3.9 ×106 CD34+ cells/70 kg,P = .165. Red cell depletion from SCT products was not possible by using hydroxyethyl starch sedimentation but was achievable with ammonium chloride lysis. There was no evidence of gelling of SCT products after thaw, and no difference in cell recovery was seen among red cell–depleted versus nondepleted products. Cryopreservation in 5% dimethyl sulfoxide/6% pentastarch was associated with superior cell recovery (both SCT and control subjects) compared with 10% dimethyl sulfoxide (P = .001). The study concluded that filgrastim mobilization, large volume apheresis, processing, and cryopreservation appears to be safe in donors with SCT, allowing PBSC use for transplantation in patients with sickle cell anemia.
Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells
Authors: Wiewrodt Rainer , Thomas Anu P. , Cipelletti Luca , Christofidou-Solomidou Melpo , Weitz David A. , Feinstein Sheldon I. , Schaffer David , Albelda Steven M. , Koval Michael , Muzykantov Vladimir R.
Published: July 2002

Cell-selective intracellular targeting is a key element of more specific and safe enzyme, toxin, and gene therapies. Endothelium poorly internalizes certain candidate carriers for vascular immunotargeting, such as antibodies to platelet endothelial cell adhesion molecule 1 (PECAM–1). Conjugation of poorly internalizable antibodies with streptavidin (SA) facilitates the intracellular uptake. Although both small and large (100-nm versus 1000-nm diameter) anti-PECAM/SA–beta galactosidase (SA–β-gal) conjugates bound selectively to PECAM-expressing cells, only small conjugates showed intracellular accumulation of active β-gal. To study whether size of the conjugates controls the uptake, a series of anti-PECAM/SA and anti-PECAM/bead conjugates ranging from 80 nm to 5 μm in diameter were produced. Human umbilical vein endothelial cells and PECAM-transfected mesothelioma cells internalized 80- to 350-nm anti-PECAM conjugates, but not conjugates larger than 500 nm. Further, size controls intracellular targeting of active therapeutic cargoes in vitro and in vivo. Small anti-PECAM/DNA conjugates transfected target cells in culture 5-fold more effectively than their large counterpart (350- versus 4200-nm diameter). To evaluate the practical significance of the size-controlled subcellular addressing, we coupled glucose oxidase (GOX) to anti-PECAM and antithrombomodulin. Both types of conjugates had equally high pulmonary uptake after intravenous injection in mice, yet only small (200- to 250-nm), not large (600- to 700-nm), GOX conjugates caused profound oxidative vascular injury in the lungs, presumably owing to intracellular generation of H2O2. Thus, engineering of affinity carriers of specific size permits intracellular delivery of active cargoes to endothelium in vitro and in vivo, a paradigm useful for the targeting of drugs, genes, and toxins.
p14ARF nuclear overexpression in aggressive B-cell lymphomas is a sensor of malfunction of the common tumor suppressor pathways
Authors: Sánchez-Aguilera Abel , Sánchez-Beato Margarita , Garcı́a Juan F. , Prieto Ignacio , Pollan Marina , Piris Miguel A.
Published: July 2002

p14ARF, the alternative product from the humanINK4a/ARF locus, antagonizes Hdm2 and mediates p53 activation in response to oncogenic stimuli. An immunohistochemical study of p14ARF expression in 74 samples of aggressive B-cell lymphomas was performed, demonstrating an array of different abnormalities. A distinct nucleolar expression pattern was detected in nontumoral tissue and a subset of lymphomas (50/74). In contrast, a group of cases (8/74) showed absence of p14ARF expression, dependent either on promoter hypermethylation or gene loss. Additionally, 16 out of 74 cases displayed an abnormal nuclear p14ARF overexpression not confined to the nucleoli, as confirmed by confocal microscopy, and that was associated with high levels of p53 and Hdm2. A genetic study of these cases failed to show any alteration in the p14ARF gene, but revealed the presence of p53 mutations in over 50% of these cases. An increased growth fraction and a more aggressive clinical course, with a shortened survival time, also characterized the group of tumors with p14ARF nuclear overexpression. Moreover, this p14ARF expression pattern was more frequent in tumors displaying accumulated alterations in the p53, p16INK4a, and p27KIP1 tumor supressors. These observations, together with the consideration of the central role of p14ARF in cell cycle control, suggest that p14ARF abnormal nuclear overexpression is a sensor of malfunction of the major cell cycle regulatory pathways, and consequently a marker of a high tumor aggressivity.
Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab
Authors: Goldberg Stuart L. , Pecora Andrew L. , Alter Robert S. , Kroll Mark S. , Rowley Scott D. , Waintraub Stanley E. , Imrit Kavita , Preti Robert A.
Published: July 2002

Efforts to reduce relapse of non-Hodgkin lymphoma after autologous transplantation have included ex vivo stem cell selection and/or peritransplantation immunotherapy. The late infectious and immunologic consequences of these maneuvers are not well understood, although an increase in early cytomegaloviral disease after CD34+ stem cell selection and an alteration in immunoglobulin and T-cell recovery after peritransplantation rituximab has been noted. We report the first 2 cases of progressive multifocal leukoencephalopathy caused by JC papovavirus after autologous peripheral blood stem cell transplantation and a case each of cytomegalovirus retinitis and pneumonitis. All 4 patients experienced significant impairment of CD4 T-cell recovery, placing them at risk for these unusual viral infections. The clustering of cases is concerning because all occurred shortly after the introduction of peritransplantation rituximab into treatment protocols (4 of 62 immunotherapy recipients compared with 0 of 276 without; z = 3.595;P < .001), although a direct association with this CD20 B-cell–directed therapy remains speculative.
Allogenic fetal liver cells have a distinct competitive engraftment advantage over adult bone marrow cells when infused into fetal as compared with adult severe combined immunodeficient recipients
Authors: Taylor Patricia A. , McElmurry Ronald T. , Lees Christopher J. , Harrison David E. , Blazar Bruce R.
Published: July 2002

In utero transplantation (IUT) is becoming a viable option for the treatment of various immune and metabolic disorders diagnosed early in gestation. In this study, donor fetal liver cells had a 10-fold competitive engraftment advantage relative to adult bone marrow in allogeneic fetal severe combined immunodeficient (SCID) recipients compared with adult recipients. In contrast, adult bone marrow cells engrafted slightly better than fetal liver cells in allogeneic adult SCID transplant recipients. By using different ratios of fetal and adult cell mixtures, fetal liver cells repopulated 8.2 times better than adult bone marrow cells in fetal recipients, but only 0.8 times as well in adult recipients. Fetal SCID recipients were more permissive to an allogeneic donor graft than adult recipients. These data indicate that the recipient microenvironment may regulate the engraftment efficiency of a given stem cell source and suggest that the use of cord blood should be tested in clinical IUT.
The significance of heparin-coated veno-venous bypass circuits in liver transplantation
Authors: Scholz Tim , Solberg Rigmor , Okkenhaug Cecilie , Videm Vibeke , Gallimore Michael J , Mathisen Øystein , Mollnes Tom E , Bergan Anstein , Søreide Odd , Klintmalm Göran B , Aasen Ansgar O
Published: July 2002

We studied the effects of veno-venous bypass (VVBP) circuit surface heparinization on the activation of the plasma defence systems (coagulation, fibrinolysis, kallikrein-kinin and complement) and leukocyte activation in a prospective randomized study in 20 patients during and 1 day after liver transplantation (OLT). To our knowledge, this is the first study of this kind where the possible benefits of surface heparinization of the VVBP circuit in OLT have been investigated. Twenty patients were randomized to either heparin-coated (HC) VVBP equipment or to otherwise identical noncoated (NC) circuits. Five blood samples were drawn during the OLT procedure: one just before VVBP, three during VVBP and one 5 min after portal venous reperfusion (PVR). A further sample was taken 1 day after the operation. Components of the blood coagulation, fibrinolytic and kallikrein-kinin systems were analysed using functional assays (chromogenic peptide substrate assays) or enzyme immunoassays (EIA). Complement system factors and granulocyte activation, represented by myeloperoxidase (MPO) release, were analyzed by EIA. Activation of the plasma defence systems occurred in both groups at an early stage during OLT and a further activation occurred 5 min after PVR. MPO levels were slightly elevated 5 min after PVR. However, no significant differences between the two groups were observed. Significant activation of the humoral defense systems was found in both groups during OLT. A considerably larger study, including at least 330 patients, is necessary to fully assess the possible benefits of surface heparinization of the VVBP circuit.