bluuebunny/crossref_metadata_2025 huggingface dataset:
GENERALIZED CALABI–YAU STRUCTURES, K3 SURFACES, AND B-FIELDS
Authors: HUYBRECHTS DANIEL
Published: January 2005

Generalized Calabi–Yau structures, a notion recently introduced by Hitchin, are studied in the case of K3 surfaces. We show how they are related to the classical theory of K3 surfaces and to moduli spaces of certain SCFT as studied by Aspinwall and Morrison. It turns out that K3 surfaces and symplectic structures are both special cases of this general notion. The moduli space of generalized Calabi–Yau structures admits a canonical symplectic form with respect to which the moduli space of symplectic structures is Lagrangian. The standard theory of K3 surfaces implies surjectivity of the period map and a weak form of the Global Torelli theorem.
DENOTATIONAL SEMANTICS OF AN HPF-LIKE DATA-PARALLEL LANGUAGE MODEL
Authors: GUO MINYI
Published: January 2005

It is important for programmers to understand the semantics of a programming language. However, little work has been done about the semantic descriptions of HPF-like data-parallel languages. In this paper, we first define a simple language [Formula: see text], which includes the principal facilities of a data-parallel language such as HPF. Then we present a denotational semantic model of [Formula: see text]. It is useful for understanding the components of an HPF-like language, such as data alignment and distribution directives, forall data-parallel statements.
ELECTRORHEOLOGICAL BEHAVIOR OF CARBONACEOUS PARTICLE-BASED SUSPENSIONS
Authors: KIM J. W. , CHOI H. J. , YOON S. H. , JHON M. S.
Published: January 2005

Using three different carbonaceous particles, we investigated the electrical and rheological properties of several ER fluids. Each of the carbonaceous particles, prepared from different treatment methods, possesses a different oxygen content or degree of crystallinity. These materials were prepared from mesophase pitch and were cationically polymerized with naphthalene and HF/BF 3 at high temperature (500~700° C ). Special focus was placed on the variables affecting ER properties, including current density, temperature, electric field strength, and volume fraction of the particles. Rheological properties were measured by a rotational rheometer equipped with a high voltage generator. To investigate the durability of the carbonaceous ER fluids, we also measured changes in shear stress, shear viscosity, and current density at the share rate of 50 sec -1 and different temperatures (from 20 to 100°C). Good thermal and electrical stability of the carbonaceous particle-based ER suspensions were observed.
TRANSIENT BEHAVIOR OF THE MICROSTRUCTURE OF ELECTRORHEOLOGICAL FLUIDS IN SHEAR FLOW MODE
Authors: VIEIRA S. L. , NAKANO M. , HENLEY S. , FILISKO F. E. , NETO L. B. POMPEO , ARRUDA A. C. F.
Published: January 2005

It was reported that under the simultaneous stimulus of an electric field and shear, the particles in an ER fluid form lamellar formations in the direction of shear (adhered to one of the electrodes) which may be responsible for the ER activity more than the strength of the chains. In this way, it would be expected that the shear stress should change consistently with the morphology of the formations. In this work we studied the effect of shearing time, electric field strength and shear rate on the shear stress. We suggest that changes on shear stress with time are due to changes of the morphology of the lamellar formations.
MECHANICAL PROPERTIES OF AN ER FLUID IN TENSILE, COMPRESSION AND OSCILLATORY SQUEEZE TESTS
Authors: VIEIRA S. L. , NAKANO M. , OKE R. , NAGATA T.
Published: January 2005

In this work, the mechanical properties of an anhydrous electrorheological fluid made of carbonaceous particles dispersed in silicone oil were determined in tensile, compression and oscillatory squeeze tests. The mechanical tests were carried out on a Mechanical Testling Machine and the device developed for measuring the ER properties was composed of two parallel steel electrodes between which the ER fluid was placed. The mechanical properties were measured for different DC electric field strengths, velocity and initial gap between the electrodes, and the ERF was tested in two different ways: (a) the fluid was placed between the electrodes (configuration 1) and (b) the electrodes were immersed inside the ERF (configuration 2). The results showed that the ER fluid is more resistant to compression than to tensile, and that the shape of the tensile stress-strain curve and the tensile strength varies with the electric field strength and the initial gap between the electrodes. The compressive stress increased with the increase of the electric field strength and with the decrease of the gap size and upper electrode velocity. In oscillatory test, for both configurations 1 and 2, increasing the oscillation frequency f and the number of cycles N produced a decrease of the damping performance of the ER fluid. Besides this, the damping force of each cycle in oscillatory tests increased with N. The electric field also played an important role on the shape of the hysteresis loop (stress as a function of fluid strain) for both configurations.
DAMPING CHARACTERISTICS OF MR FLUIDS IN LOW MAGNETIC FIELDS
Authors: NISHIYAMA HIDEYA , OYAMA TADAMASA , FUJITA TOYOHISA
Published: January 2005

The cluster structure is visualized and the physical properties of new two types of nano MR fluids are measured in the applied magnetic fields. Correlating to these measurements, the damping characteristics of an oscillating flat plate immersed in two types of nano MR fluids such as damping amplitude, phase difference, viscous damping coefficient and viscous drag force acted on a flat plate are experimentally clarified, comparing with those of commercial magnetic fluid from the fluiddynamic points of view. It is shown that the resonance of damping amplitude and phase difference are very sensitive to the applied magnetic field, and further the damping effect of MR fluid is about ten times stronger than that of the commercial magnetic fluid even in low magnetic fields of 50–100 Gauss due to the robust cluster formation.
DYNAMIC SIMULATION STUDIES OF STRUCTURAL FORMATION AND TRANSITION IN ELECTRO-MAGNETO-RHEOLOGICAL FLUIDS
Authors: Wang Zuowei , Fang Haiping , Lin Zhifang , Zhou Luwei
Published: January 2005

The computer simulation method has been used to study the structural formation and transition of electro-magneto-rheological (EMR) fluids under compatible electric and magnetic fields. When the fields are applied simultaneously and perpendicularly to each other, the particles rapidly arrange into two-dimensional close-packed layer structures parallel to both fields. The layers then combine together to form thicker sheer-like structures, which finally relax into three-dimensional close-packed structure with the help of the thermal fluctuations. On the other hand, if the electric field is applied firstly to induce the body-centered tetragonal (BCT) columns in the system, and then the magnetic field is applied in the perpendicular direction, the BCT to face-centered cubic (FCC) structure transition is observed in very short time. Following that, the structure keeps on evolving due to the demagnetization effect and finally form the three-dimensional close-packed structures.
EFFECT OF THREE FUNCTIONAL GROUPS ON ELECTRORHEOLOGY
Authors: KAWAI A. , IKAZAKI F.
Published: January 2005

Electrorheology (ER) was studied for 3 fluids consisting of dispersoids having different functional groups and the same alkyl chain ( C 16 H 33-X; X=-OH, -COOH, -CN) dispersed in dimethylsilicone oil. Fluids changed from dispersed to homogeneous with increasing operating temperature because dispersoids melted at higher temperatures. Both the ER effect and dielectric properties changed drastically with the change from dispersed to homogeneous. Both their ER effect and Δε′ increased with temperature below their melting points, becoming almost zero above their melting points. The ER effect of -OH was the highest and that of -CN lowest. The ER effect of fluids were largely explained by Δε′, the difference in dielectric constant ε′ at 102 and 105 Hz.
PLANETARY SEISMOLOGY
Authors: Lognonné Philippe
Published: January 2005

▪ Abstract  Contrary to Earth, the interior of terrestrial planets is poorly known. This is mainly related to the lack of seismic data and of planetary seismic networks on these planets. So far, despite several attempts, only the Apollo Seismic Network has returned seismic information from the Moon. But even in this case, very few seismic signals were recorded after a propagation path through the deep interior and core owing to a hemispheric distribution of the stations on the near side and to a probably strongly attenuating lower mantle. This review presents the main results achieved by the analysis of the Apollo seismic data and the associated constraints on the internal structure of the Moon. It then presents the current knowledge on the Martian interior, the seismic activity of the planet, and possible source of seismic noise. This information can be used for preparing future Martian seismic network missions. A short review on existing space-qualified instruments and on possible seismic missions toward other telluric bodies, such as Venus, the giant planets' satellites, or small bodies, is then given.
THE B7 FAMILY REVISITED
Authors: Greenwald Rebecca J. , Freeman Gordon J. , Sharpe Arlene H.
Published: January 2005

▪ Abstract  The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cell–dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.
TOWARD AN UNDERSTANDING OF NKT CELL BIOLOGY: Progress and Paradoxes
Authors: Kronenberg Mitchell
Published: January 2005

▪ Abstract  Natural killer T (NKT) cells constitute a conserved T cell sublineage with unique properties, including reactivity for a synthetic glycolipid presented by CD1d, expression of an invariant T cell antigen receptor (TCR) α chain, and unusual requirements for thymic selection. They rapidly produce many cytokines after stimulation and thus influence diverse immune responses and pathogenic processes. Because of intensive research effort, we have learned much about factors promoting the development and survival of NKT cells, regulation of their cytokine production, and the means by which they influence dendritic cells and other cell types. Despite this progress, knowledge of the natural antigen(s) they recognize and their physiologic role remain incomplete. The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and we cannot predict which will occur. Despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.
Generalization of Motor Learning Based on Multiple Field Exposures and Local Adaptation
Authors: Malfait Nicole , Gribble Paul L. , Ostry David J.
Published: January 2005

Previous studies have used transfer of learning over workspace locations as a means to determine whether subjects code information about dynamics in extrinsic or intrinsic coordinates. Transfer has been observed when the torque associated with joint displacement is similar between workspace locations—rather than when the mapping between hand displacement and force is preserved—which is consistent with muscle- or joint-based encoding. In the present study, we address the generality of an intrinsic coding of dynamics and examine how generalization occurs when the pattern of torques varies over the workspace. In two initial experiments, we examined transfer of learning when the direction of a force field was fixed relative to an external frame of reference. While there were no beneficial effects of transfer after training at a single location ( experiments 1 and 2), excellent performance was observed at the center of the workspace after training at two lateral locations ( experiment 2). Experiment 3 and associated simulations assessed the characteristics of this generalization. In these studies, we examined the patterns of transfer observed after adaptation to force fields that were composed of two subfields that acted in opposite directions. The experimental and simulated data are consistent with the idea that information about dynamics is encoded in intrinsic coordinates. The nervous system generalizes dynamics learning by interpolating between sets of control signals, each locally adapted to different patterns of torques.
Shaking the Dust off the Markan Mission Discourse
Authors: Rogers T. J.
Published: January 2005

The mission discourse in Mark has produced no exegetical consensus among scholars, particularly with regard to the list of items in vv. 8-9 and the dust-shaking gesture in v. 11. The author critiques the most commonly offered interpretations and argues that the pericope is best understood when read in the context of ancient hospitality norms, implied in v. 10. The list of items restricts the self-sufficiency of missionaries to the point of requiring them to receive the hospitality commanded in the following verse. Likewise, the dust-shaking is best understood as a testimony that their feet were not washed according to the customs of hospitality. The plausibility of this interpretation is then tested against the social-historical context of Christianity in the first century.
Elder Care Exchanges in a Caribbean Village
Authors: Kelley Lisa Skemp
Published: January 2005

Caregiver gender research often translates into caregiver accounts of the care they provide for an elder parent or spouse, limiting an understanding of other communitymembers’involvement and the actual gendered elder care activities performed and caregiver benefits received. This article describes women’s and men’s actual involvement in elder care. These findings are part of a fourphase ethnographic community study that includes in-depth network analysis of elder households. One-hundred and forty-three informal adult caregivers assisted 15 elders in obtaining the things they needed to live, providing 244 care activities. One-hundred and three women provided 194 care activities, and 40 men performed 50 care activities. In exchange, the frail elders gave the women caregivers 132 benefits and the men 54 benefits. Women and men differed in the amount and type of care involvement, as well as their motivational mechanisms for involvement in elder care.
Effects of a Physical Activity Intervention for Women
Authors: Peterson Jane Anthony , Yates Bernice C. , Atwood Jan R. , Hertzog Melody
Published: January 2005

Physical activity is associated with health and reduced mortality risk, yet only15% ofU.S. adults achieve adequate activity. This study is an experimental repeated measures nested design randomizing two similar rural communities to investigate the effectiveness of the Heart and Soul Physical Activity Program (HSPAP) (Peterson, 2002) in promoting physical activity in midlife women (n =42) aged 35 to 65 years. The HSPAP, an innovative church-based health promotion intervention, is conceptualized in social support and designed to increase physical activity, energy expenditure (EE), and cardiorespiratory fitness (VO2 max), measured over time. A significant interaction (p < .001) was found for EE in one HSPAP group increasing their EE by 1,010 kcals/week. HSPAP participants increased their VO2 max level by 75% (p < .001) and 10%; comparison groups stayed the same or declined 16%. Study results provide preliminary support for the HSPAP intervention as an effective treatment to improve physical activity levels in sedentary, rural, midlife women.
The Schematic Development of Old Testament Chronography: Towards an Integrated Model
Authors: Northcote Jeremy
Published: January 2005

The chronological figures in the Old Testament have been of considerable interest to early and modern scholars, but there has been little success in developing an overarching model to account for their historical development. Through a synthesis of past approaches and new insights, an attempt is made in this article to develop a model that explains the emergence of Old Testament chronology and accounts for the divergences that exist in the figures found in different Old Testament textual traditions. The position taken is that Old Testament chronology was, from its very beginnings, largely schematic in form. Further, it is argued that subsequent adjustments to the chronology were motivated mainly by changing schematic interests rather than ‘rational’ concerns such as the resolution of internal anachronisms or ‘secret’ systems of calendar reckoning (as some scholars have proposed). These schematic considerations are viewed in terms of the changing political, theological and sectarian interests of Palestine and the diaspora between the sixth century BCE and the second century BCE.
The Role of Exchange in Ancient Mediterranean Religion and Its Implications for Reading Genesis 18-19
Authors: Bolin Thomas M.
Published: January 2005

This article reads Genesis 18-19 in the light of the principal of exchange at work in ancient religious belief concerning divine justice. Genesis 18.1-15 and 19.1-29, as examples of the well-worn tale of the divine visitor, are narrative expressions of confidence in a divine justice that rewards the kind and punishes the inhospitable. In the dialogue of 18.6-33, Abraham explicitly raises the question of divine justice, but complicates it by also exploring the possibility of divine mercy. The second divine visitor tale in Gen. 19.1-29, in which Sodom is justly destroyed while Lot is spared out of mercy, shows that Yahweh operates according to more stringent ideas of justice than humanity would wish.
Hosea 1-2 and the Search for Unity
Authors: Mitchell Matthew W.
Published: January 2005

Hosea’s early chapters have borne the weight of much of the critical commentary and scholarly discussion of the book throughout the history of its interpretation. Although much of this attention has been the result of what Yvonne Sherwood has termed the ‘critical obsession with Hosea’s marriage’, and its related assumptions about the biographical basis of this material, much of this scrutiny has also focused on the issues of genre and literary structure. Hosea is affirmed as a unified work of exceptional quality, in spite of the initial impression the text often gives of being comprised of distinct and loosely connected units whose meaning is obscured by an admittedly corrupt textual tradition. Chapters 1-2 are often described as a microcosm of this exceptionally subtle book, although this study’s close examination of these chapters calls scholarly affirmations of Hosea’s unity into question.
Lamb Wave Propagation-based Damage Identification for Quasi-isotropic CF/EP Composite Laminates Using Artificial Neural Algorithm: Part I - Methodology and Database Development
Authors: Su Zhongqing , Ye Lin
Published: January 2005

A guided Lamb wave-based damage identification scheme and an online structural health monitoring (online-SHM) system with an integrated piezoelectric actuator-sensor network are developed. The proposed methodology is applied to the quantitative diagnosis of through-hole-type defect in the CF-EP quasi-isotropic laminate with the aid of an artificial neural network algorithm. For this purpose, a variety of composite laminates with stochastic damages are considered, and the corresponding three-dimensional dynamic FEM simulations are conducted. To describe a Lamb wave excited by the PZT actuator, models for both the piezoelectric actuator and sensor coupled with the composite laminates are established. A wavelet transform-based signal processing package (SPP) is devised to purify the acquired wave signals, and further extract characteristics from the energy spectra of Lamb waves over the time-scale domain. A concept of ‘digital damage fingerprints’ is introduced, with which a damage parameters database (DPD) is constructed and used to offline train a multilayer feedforward neural network, supervised by an error-back propagation (BP) neural algorithm. Such an identification technique is then validated, to be described in the second part of this study.
Lamb Wave Propagation-based Damage Identification for Quasi-isotropic CF/EP Composite Laminates Using Artificial Neural Algorithm: Part II - Implementation and Validation
Authors: Su Zhongqing , Ye Lin
Published: January 2005

Active transducer networks using distributed piezoelectric actuator/sensor were designed in terms of a concept of ‘Standard Sensor Unit’ (SSU). Functionally integrating the artificial neural networks well-trained by Damage Parameters Database (DPD) developed in Part I, an active online structural health monitoring (SHM) system was configured on a VXI platform, which was then validated by quantitatively identifying hole-type defects in quasi-isotropic [0/45/-45/90]s CF/EP (T650/F584) composite laminates. The system has exhibited excellent ability to quantitatively assess the damaged parameters, including presence, location, geometric identity, and orientation. Additionally, the reliability and performance of the SHM system on the inherent network configurations, such as architecture, training pattern, training function, and distribution of transducers, were also evaluated.
A Small-sized Variable-damping Mount using Magnetorheological Fluid
Authors: Ahn Young Kong , Yang Bo-Suk , Ahmadian Mehdi , Morishita Shin
Published: January 2005

This paper deals with an application study of a magnetorheological (MR) fluid to a small-sized variable-damping mount for precision equipment of automobiles. MR fluids are a class of functional fluids with a controllable yield stress due to the applied magnetic field strength. A typical MR fluid is a suspension where pure iron particles of 1-20 mm diameter are dispersed in a liquid such as mineral or silicone oil, at a concentration of 20-40 vol%. A variable-damping mount filled with an MR fluid is combined with a magnetic coil at the bottom, and its performance is investigated experimentally and its damping mechanism is estimated analytically.
Analytical and Experimental Study of the Response of a Suspension System with a Magnetorheological Damper
Authors: Shen Y. , Golnaraghi M. F. , Heppler G. R.
Published: January 2005

A single-degree-of-freedom suspension system with a magnetorheological (MR) damper is studied. A Bouc-Wen hysteretic model is adopted to represent the nonlinear hysteretic damping force of an MR damper. The model parameter identification process is carried out based on the experimental data. The equivalent linearization and the averaging methods are employed to simplify the hysteretic nonlinear model of the system, and to obtain the system response under sinusoidal base excitation. The results obtained by these two approximate methods are compared with the results obtained from the experiments and the numerical simulation method when a swept sine excitation with amplitudes of 0.5 and 0.75 mm is applied to the system. The comparison shows that the results obtained by the equivalent linearization method and the averaging method are very similar and have a good agreement with both the experimental and the numerical results. Moreover, the effects of the hysteretic model parameters are investigated after the system dynamical equations are nondimensionalized.
Adaptive Simultaneous Precision Positioning and Vibration Control of Intelligent Composite Structures
Authors: Ma Kougen , Ghasemi-Nejhad Mehrdad N.
Published: January 2005

This paper presents an adaptive control scheme for simultaneous precision positioning and vibration suppression of intelligent structures. First, the structure and materials system of an active composite panel with piezoelectric ceramic patches are introduced. An adaptive control scheme, which consists of an adaptive feedback and two adaptive feedforward controllers, is then proposed. The two adaptive feedforward controllers are responsible, one for precision positioning and the other for vibration suppression, and the adaptive feedback controller affects both precision positioning and vibration suppression. Two PID feedback controllers and the proposed adaptive control scheme are experimentally studied on the active composite panel under harmonic and random disturbances, demonstrating that (a) for the PID feedback control, the controller gains should be chosen carefully to make a tradeoff between position tracking and vibration suppression, and the positioning accuracy varies for different disturbances due to residual vibrations; and (b) for the proposed adaptive control scheme, the vibration is entirely suppressed and the positioning accuracy is consistently excellent no matter what kind of disturbance is encountered, the relative steady state error is 3%, and the controller can adjust its weights to adapt to the changes of the command and the external disturbances.
The Study of Policing
Authors: Manning Peter K.
Published: January 2005

The police are legitimate, bureaucratically articulated organizations that stand ready to use force to sustain political order. Anglo-American policing (AAP) is democratic policing: It eschews torture, terrorism, and counter-terrorism, is guided by law, and seeks minimal damage to civility. Research on AAP, a policing type developed by adaptation rather than conquest (refined by Peel and exported to Canada, New Zealand, Australia, and the United States) in the United Kingdom and the United States, is reviewed. Police studies, like policing itself, is based on material, political, and cultural interests that pattern the production and distribution of knowledge. Interests in the United States and the United Kingdom are summarized, and the origins, key figures in studies of policing, the emergence of police scholarship, and some differences between the United Kingdom and the United States in funding, education, and training are outlined. There remain tensions between public pressures for short-term-funded research and theoretically grounded scholarship. The paper ends with reflections on the future of police studies.
“Horses for Courses” and “Thin Blue Lines”: Community Policing in Transitional Society
Authors: Brogden Mike
Published: January 2005

The export of policing models from the West has a long history. Current export processes are dominated by the transfer of community policing (COP) models from Anglo-American jurisdictions to societies currently regarded as undergoing a transitional process. The latter are frequently characterized by rising recorded crime rates and a delegitimation of their own police institutions. Consequently, COP appears to offer a welcome respite, especially when encouraged not just by policing missionaries from the West and donor cash but also by a variety of nongovernmental organizations that see COP effectiveness as a human rights resolution to police abuse. Using secondary data from a range of failed and transitional societies, this article challenges the motives, processes, and consequences of the export of such a Western policing model. The end result, from the preliminary evidence, seems to be one of deepening social schism in the country of import. COP is irrelevant to many such societies.
Building a Global Police Studies Community
Authors: Marenin Otwin
Published: January 2005

Policing has become decentered from the state as substate and transnational developments have shifted some of the roles and authority for policing to new social and international groups and agencies. At the international level, a number of regime communities (e.g., scholars, nongovernmental organizations, police leaders, transnational policy makers, and policy think tanks) have actively promoted the emergence of a democratic, international policing regime and its adoption by states and police forces in transitional, failed, and developed countries. Recent developments are described, and their implications for the practices and the study of policing are assessed.
Von Willebrand factor accelerates platelet adhesion and thrombus formation on a collagen surface in platelet-reduced blood under flow conditions
Authors: Tomokiyo Kazuhiko , Kamikubo Yuichi , Hanada Takako , Araki Tatsuya , Nakatomi Yasushi , Ogata Yoichi , Jung Stephanie M. , Nakagaki Tomohiro , Moroi Masaaki
Published: January 2005

Plasma von Willebrand factor (VWF) has been identified as an indispensable factor for platelet adhesion and thrombus formation on a collagen surface under flow conditions. VWF binds to collagen and then tethers platelets to the collagen surface through interaction with platelet glycoprotein Ib and also contributes to the thrombus formation on the collagen surface. In the present study, we demonstrated that the addition of VWF/factor VIII complex or purified VWF (> 2 ristocetin cofactor activity units/mL) increased platelet adhesion to the collagen surface in platelet-reduced blood (∼ 5 × 104 platelets/μL) to the normal level. VWF had no stimulatory effect when it was allowed to bind to the collagen surface before blood flow was initiated. Addition of an excess of FITC (fluorescein-5-isothiocyanate)–abeled VWF to platelet-reduced blood under these flow conditions demonstrated that the VWF was mainly incorporated into the platelet aggregates. These results indicated that the supplemented VWF stimulates the platelet adhesion onto the collagen surface by enhancing platelet aggregation in the platelet-reduced condition. This also suggests a possibility that supplementation of VWF to individuals with thrombocytopenia might be effective for increasing their hemostatic potential.
A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease
Authors: Fiedler Walter , Serve Hubert , Döhner Hartmut , Schwittay Michael , Ottmann Oliver G. , O'Farrell Anne-Marie , Bello Carlo L. , Allred Randy , Manning William C. , Cherrington Julie M. , Louie Sharianne G. , Hong Weiru , Brega Nicoletta M. , Massimini Giorgio , Scigalla Paul , Berdel Wolfgang E. , Hossfeld Dieter K.
Published: January 2005

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67+, phospho-Kit+, phospho–kinase domain–containing receptor–positive (phospho-KDR+), phospho–signal transducer and activator of transcription 5–positive (phospho-STAT5+), and phospho-Akt+ cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
Ligands for natural killer cell–activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias
Authors: Nowbakht Pegah , Ionescu Mihai-Constantin S. , Rohner Andreas , Kalberer Christian P. , Rossy Emmanuel , Mori Lucia , Cosman David , De Libero Gennaro , Wodnar-Filipowicz Aleksandra
Published: January 2005

Natural killer (NK) cell–mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow–derived CD34+ progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-γ, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell–mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.
Involvement of connective tissue–type mast cells in Th1 immune responses via Stat4 expression
Authors: Kataoka Tatsuki R. , Komazawa Nobuyasu , Morii Eiichi , Oboki Keisuke , Nakano Toru
Published: January 2005

Mast cells are the sentinels of immune systems and, like other immuno-competent cells, they are produced by hematopoietic stem cells. We analyzed the expression of signal transducer and activator of transcription 4 (Stat4), and investigated its role in mast cells. Murine mast cells are usually divided into 2 distinct populations by their distribution and contents of their granules: mucosal mast cells (MMCs) and connective tissue–type mast cells (CTMCs). Stat4 protein was detected in CTMCs but not in MMCs. The absence of Stat4 expression in cultured mast cells was due to the presence of Stat6. In T-helper (Th) cells, Stat4 plays an important role in Th1 shift by inducing a set of genes, such as interferon gamma (IFN-γ) and interleukin-18 receptor α subunit (IL-18Rα). As in Th1 shift, we found that Stat4 trans-activated these genes in the Stat4-expressing cultured mast cells, namely, microphthalmia transcription factor (MITF)–deficient cultured MMCs, Stat6-deficient cultured MMCs, and cultured CTMCs. Stat4 also enhanced expression of nitric oxide synthase 2 (NOS2) in CTMCs, which brought about increased levels of NO-dependent cytotoxic activity. These data indicate that expression of Stat4 in CTMCs plays an important role on Th1 immune responses.
A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival
Authors: Pearse Roger N. , Swendeman Steven L. , Li Ying , Rafii Dahlia , Hempstead Barbara L.
Published: January 2005

Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the clonal expansion of malignant plasma cells and is frequently associated with chromosomal translocations placing an oncogene under the control of the immunoglobulin heavy chain enhancer. Despite these pathogenic translocations, MM cells remain dependent on external cues for survival. We present evidence that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), contribute to these survival cues. MM cells express TrkB, and respond to BDNF by activating mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase–a PI3K target (PI3K/Akt) signaling cascades. Addition of BDNF protects human MM cell lines (HMCLs) from apoptosis induced by dexamethasone or bortezomib and prolongs the survival of primary MM cells cultured alone or with human bone marrow (BM) stroma. As BDNF and TrkB are expressed by osteoblasts, stromal cells, and endothelial cells within the BM microenvironment, a BDNF-TrkB axis may be critical to the interactions of MM with bone and stroma that contribute to MM tumor progression. Finally, BDNF is expressed by malignant plasma cells isolated from a subset of patients with MM, as well as by most HMCLs, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM.
Activity and specificity of toxin-related mouse T cell ecto–ADP-ribosyltransferase ART2.2 depends on its association with lipid rafts
Authors: Bannas Peter , Adriouch Sahil , Kahl Sarah , Braasch Fenja , Haag Friedrich , Koch-Nolte Friedrich
Published: January 2005

Adenosine diphosphate (ADP)–ribosyl-transferases (ARTs) transfer ADP-ribose from nicotinamide adenine dinucleotide (NAD) onto target proteins. T cells express ART2.2, a toxin-related, glycosylphosphatidylinositol (GPI)–anchored ecto-enzyme. After the release of NAD from cells, ART2.2 ADP-ribosylates the P2X7 purinoceptor, lymphocyte function–associated antigen (LFA-1), and other membrane. Using lymphoma transfectants expressing either ART2.2 with its native GPI anchor (ART2.2-GPI) or ART2.2 with a grafted transmembrane anchor (ART2.2-Tm), we demonstrated that ART2.2-GPI but not ART2.2-Tm associated with glycosphingolipid-enriched microdomains (lipid rafts). At limiting substrate concentrations, ART2.2-GPI exhibited more than 10-fold higher activity than ART2.2-Tm. On intact cells, ART2.2-GPI ADP-ribosylated a small number of distinct target proteins. Strikingly, the disruption of lipid rafts by cyclodextrin or membrane solubilization by Triton X-100 increased the spectrum of modified target proteins. However, ART2.2 itself was a prominent target for ADP-ribosylation only when GPI anchored. Furthermore, cholesterol depletion or detergent solubilization abolished the auto-ADP-ribosylation of ART2.2. These findings imply that ART2.2-GPI, but not ART2.2-Tm, molecules are closely associated on the plasma membrane and lend support to the hypothesis that lipid rafts exist on living cells as platforms to which certain proteins are admitted and others are excluded. Our results further suggest that raft association focuses ART2.2 on specific targets that constitutively or inducibly associate with lipid rafts.
PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia
Authors: Wolff Nicholas C. , Veach Darren R. , Tong William P. , Bornmann William G. , Clarkson Bayard , Ilaria Robert L.
Published: January 2005

Imatinib mesylate is highly effective in newly diagnosed chronic myeloid leukemia (CML), but BCR/ABL (breakpoint cluster region/abelson murine leukemia)–positive progenitors persist in most patients with CML treated with imatinib mesylate, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and antileukemic properties of PD166326, one of the most potent members of the pyridopyrimidine class of protein tyrosine kinase inhibitors. In mice with the CML-like disease, PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose and demonstrated marked antileukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a white blood cell (WBC) count less than 20.0 × 109/L (20 000/μL) at necropsy, compared with only 8% of imatinib mesylate–treated animals. Further, two thirds of PD166326-treated animals had complete resolution of splenomegaly, compared with none of the imatinib mesylate–treated animals. Consistent with its more potent antileukemic effect in vivo, PD166326 was also superior to imatinib mesylate in inhibiting the constitutive tyrosine phosphorylation of numerous leukemia-cell proteins, including the src family member Lyn. PD166326 also prolonged the survival of mice with imatinib mesylate–resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective antileukemic activity. Clinical development of PD166326 or a related analog may lead to more effective drugs for the treatment of de novo and imatinib mesylate–resistant CML.
Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells
Authors: Lee Young-Ran , Yang In-Ho , Lee Young-Hee , Im Sun-A , Song Sukgil , Li Hong , Han Kun , Kim Kyungjae , Eo Seong Kug , Lee Chong-Kil
Published: January 2005

The main targets for the immunosuppressive calcineurin inhibitors, cyclosporin A (CsA) and tacrolimus, have been considered to be activated T cells, but not antigen-presenting cells. Here we demonstrate that CsA and tacrolimus, but not rapamycin, inhibit major histocompatibility complex (MHC)–restricted antigen presentation in dendritic cells (DCs). Microencapsulated ovalbumin (OVA) was efficiently captured, processed, and presented on both class I MHC molecules (cross-presentation) as well as on class II MHC molecules. Addition of CsA and tacrolimus, but not rapamycin, to cultures of DCs inhibited both the class I processing pathway and the class II processing pathway of exogenous OVA. In addition, CsA and tacrolimus, but not rapamycin, also inhibited the classic class I processing pathway of endogenous OVA. CsA and tacrolimus did not inhibit presentation of exogenously added OVA peptide, SIINFEKL, phagocytic activity of DCs, or the total level of expression of class I MHC (H-2Kb) molecules. CsA and tacrolimus, however, inhibited profoundly the expression of SIINFEKL-H-2Kb complexes in OVA-phagocytized DCs. These results demonstrate clearly that CsA and tacrolimus inhibit intracellular processing events of antigens, and further suggest that the immunosuppressive activity of CsA and tacrolimus is at least in part due to inhibition of antigen processing pathways.
Platelet‐Activating Factor Receptor Signals in Rat Osteoblasts during Spaceflight
Authors: KUMEI YASUHIRO , MORITA SADAO , NAKAMURA HIROSHI , AKIYAMA HIDEO , KATANO HISAKO , SHIMOKAWA HITOYATA , OHYA KEI'ICHI
Published: January 2005

Abstract: The platelet‐activating factor (PAF) is a lipid mediator. The G‐protein‐coupled receptor of PAF (PAF‐R) is activated by inflammatory and stressful conditions in numerous cell types. PAF/PAF‐R is involved in apoptotic and antiapoptotic processes. We examined microgravity effects on the expression of PAF‐R and second messengers in rat osteoblasts. The PAF‐R signals are transmitted via arachidonic acid, phospholipase C (PLC), protein kinase C (PKC), and mitogen‐activated protein kinase. Rat osteoblasts were cultured for 4 and 5 days aboard a space shuttle and solubilized on board. PAF‐R gene expression in flight cultures increased to 2–6‐fold higher than in ground controls. Gene expression of the G‐protein α subunit Gαq in flight cultures increased to 3‐fold and higher than in ground controls. It is known that Gaq stimulates the effecter PLCβ, activating PKC. The mRNA levels of PKCδ and PKCϑ in flight cultures were increased to 2–5‐fold higher than in ground controls. The PKCα mRNA level in flight cultures was increased to 3‐fold higher than in ground controls on the 4th day. Gene expression of catalytic and regulatory subunits of protein kinase A was suppressed in flight cultures. PKCδ and PKCϑ are novel PKCs that can be target substrates of caspases. The PAF‐R gene may act as a mechano‐sensitive gene that is involved in the apoptotic and antiapoptotic processes of osteoblasts under microgravity.
Osteoblast Responsiveness to 1α,25‐Dihydroxyvitamin D3 during Spaceflight
Authors: KUMEI YASUHIRO , MORITA SADAO , NAKAMURA HIROSHI , KATANO HISAKO , OHYA KEI'ICHI , SHIMOKAWA HITOYATA , SAMS CLARENCE F. , WHITSON PEGGY A.
Published: January 2005

Abstract: Rat osteoblasts were cultured aboard a space shuttle for 4 and 5 days. Cells were treated with 1 nM 1α,25‐dihydroxyvitamin D3 (VD) for the last 1 day. The conditioned media were harvested. Cells were solubilized with guanidine solution on board. We examined microgravity effects on the production/expression of osteocalcin, bone sialoprotein (BSP), and VD receptor (VD‐R) in osteoblasts. Under VD treatment, the osteocalcin protein level was 243 ± 117 and 1,718 ± 534 pg/μg cellular DNA in flight cultures and ground controls, respectively. Without VD treatment, the osteocalcin protein level was not different between flight cultures and ground controls. The osteocalcin mRNA level in the VD‐treated flight cultures was as low as 16% of that in ground controls. The VD‐R mRNA level in the VD‐treated flight cultures was also decreased to 16% of that in ground controls. Microgravity would suppress the VD‐inducible production of osteocalcin but not the basal productivity. The BSP mRNA level was increased by microgravity. VD/VD‐R binds to the vitamin D‐responsive element (VDRE) on the target genes. The rat osteocalcin gene is positively regulated via “enhancer” VDRE, whereas the rat BSP gene is negatively regulated via “repressor” VDRE. Microgravity might modulate osteoblast responsiveness to VD through the suppression of VD‐R.