bluuebunny/crossref_metadata_2025 huggingface dataset:
The Isoforms of Rat Natural Killer Cell Receptor NKR-P1 Display a Distinct Binding of Complex Saccharide Ligands - RETRACTED
Authors: Plíhal Ondřej , Byrtusová Pavla , Pavlíček Jiří , Mihók Ľuboslav , Ettrich Rüdiger , Man Petr , Pompach Petr , Havlíček Vladimír , Hušáková Lucie , Bezouška Karel
Published: March 2004

We wish to retract this article due to the confirmed scientific misconduct of Karel Bezouška. Based on the results of investigation of a joint ethical committee established by the Institute of Microbiology, Academy of Sciences of the Czech Republic and the Faculty of Science, Charles University in Prague, we can conclude that experiments describing binding of natural killer cell receptors to carbohydrate ligands were manipulated by Karel Bezouška. Therefore all authors, except L.M. who cannot be traced, agreed on the retraction of this paper. We apologize to all affected parties.
Phospholipid Composition of Immature Rat Myocardium Exposed to Chronic Hypoxia and the Effect of Normoxic Recovery
Authors: Novák František , Tvrzická Eva , Pelouch Václav , Ježková Jana , Smik David , Nováková Olga
Published: March 2004

Four-day-old male Wistar rats were exposed to intermittent high-altitude (IHA) hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 5 days/week, 25 exposures). The concentration of individual phospholipids (PL) and fatty acid (FA) composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and diphosphatidylglycerol (DPG) were determined in right (RV) and left (LV) ventricles of rats adapted to chronic hypoxia (40-day-old), rats after 30 days of recovery from hypoxic to normoxic conditions (70-day-old) and both age-matched controls. The adaptation to IHA hypoxia decreased the concentration of DPG in LV (by 10%) in comparison with normoxic control. In hypoxic group the proportion of linoleic acid (18:2n-6) decreased; on the contrary, the proportion of arachidonic (20:4n-6), docosapentaenoic (22:5n-3) and docosahexaenoic (22:6n-3) acids increased in PC and PE of both RV and LV. As to DPG, IHA hypoxia caused a significant decrease in the n-6/n-3 ratio due to the increase in the 22:6n-3 proportion in RV. Thirty-day-long recovery from hypoxic to normoxic conditions led to complete regression of the hypoxic effect on FA composition in all PL. No difference in FA composition of PL was observed between RV and LV in any experimental group. Numerous dietary studies with fish oil supplements confirmed cardioprotective effect of n-3 polyunsaturated FA. We suppose that their increased content in heart-membrane PL observed in this study independently on a diet might contribute to higher tolerance of chronically hypoxic myocardium to ischemic injury.
The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes
Authors: Wsól Vladimír , Szotáková Barbora , Baliharová Vendula , Šišpera Luděk , Holčapek Michal , Kolářová Lenka , Suchanová Bohumila , Kuchař Miroslav , Skálová Lenka
Published: March 2004

The phase I metabolism of quinlukast (VÚFB 19363, Q; 4-{[4-(2-quinolylmethoxy)phenyl]- sulfanyl}benzoic acid), a new antiasthmatic drug with significant antileukotriene effects, was investigated in rat microsomes and hepatocytes. Quinlukast, incubated with rat liver microsomal fraction under oxidative conditions, generated four metabolites, M2-M5. Based on comparison with synthetically prepared standards, metabolites M2 and M4 were identified as sulfoxide and sulfone of the parent compound, respectively. Metabolites M3 and M5 were identified as quinlukast dihydrodiols. For all the metabolites the apparent kinetic parameters K'm, V'max and metabolic efficiency Clint were calculated. No metabolite was found in rat liver cytosol. In vitro studies with primary cultures of isolated hepatocytes were designed to evaluate time dependent (2, 4, 8 and 24 h) and concentration dependent (0.005-0.1 mmol/l) formation of metabolites of quinlukast. Four metabolites were detected in culture medium. Three of them were identical to metabolites found in incubation of quinlukast with microsomes (M2, M3 and M5) and another, the most polar metabolite, M1, was detected. The basic metabolic pathways were proposed for quinlukast in rats.
Characterisation of Mutated Proteinases Derived from HIV-Positive Patients: Enzyme Activity, Vitality and Inhibition
Authors: Kožíšek Milan , Prejdová Jana , Souček Milan , Machala Ladislav , Staňková Marie , Linka Marek , Brůčková Marie , Konvalinka Jan
Published: March 2004

HIV protease (PR) specifically cleaves viral polyproteins to yield infectious progeny virus particles. Inactivation of PR leads to loss of virus infectivity and PR thus became an attractive pharmaceutic target. Indeed, seven protease inhibitors (PI) have been approved for clinical use to date. However, emerging resistant viral variants with reduced sensitivity to PIs become a major obstacle to successful control of viral replication. We have previously reported the design, testing and structural analysis of a pseudopeptide inhibitor, QF34, which efficiently inhibits a wide variety of PR variants. In a clinical study, we have monitored more than 100 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy including PI. In this paper we describe kinetic characterisation of two highly resistant PR species isolated from these patients. The mutated proteases accumulated as much as 14 amino acid exchanges and develop resistance to saquinavir, ritonavir, indinavir and nelfinavir with vitality value up to 150. Kinetic analyses revealed that second-generation PI lopinavir and QF34 retained their subnanomolar potency against both multidrug resistant PR variants. These results suggest a route to the design of PIs capable of inhibiting a variety of resistant PR mutants.
THEORIES OF PHASE BEHAVIOR OF COLLOIDAL SUSPENSIONS
Authors: NAVASCUÉS G. , VELASCO E. , MEDEROS L.
Published: March 2004

Colloidal suspensions are ubiquitous in nature. They also occur in many processes of industrial and technological interest. However, an understanding of the basic microscopic interactions and the rich phase behavior exhibited by colloidal suspensions is still lacking. In the present paper we give a short overview of the different statistical-mechanical approaches that have been proposed to account for the phase behavior and phase transitions occurring in systems made up of spherical colloidal particles immersed in a fluid matrix of structureless solvent particles. Effective interactions in these systems are seen to be invariably of a very short-ranged nature, and particular emphasis is put on different models that very accurately approximate these interactions. A central theme of this review is the effect of correctly incorporating the correlation structure of the colloidal system into the statistical-mechanical treatment, and how this feature very decisively affects the quality of the theoretical predictions for the colloid thermodynamics and phase behavior. Based on the importance of the correlation structure, theories relying on perturbative expressions are seen to fail to a higher or lesser extent when applied to systems of particles interacting via short-ranged potentials, and a critical discussion is provided on different proposals to overcome these difficulties. In particular, a recently proposed self-consistent nonperturbative theory is reviewed, and some of its more recent applications are shown.
NANOSTRUCTURAL ZnO FABRICATED BY VAPOR-PHASE TRANSPORT IN AIR
Authors: XU C. X. , SUN X. W. , CHEN B. J. , SUN C. Q. , TAY B. K.
Published: March 2004

Nanostructural zinc oxide has been successfully fabricated by heating the mixture of ZnO and graphite powders in air. The growth of these zinc oxide nanostructures with respect to the growing time and temperature has been studied. The morphologies and the crystal structures have been characterized by scanning electronic microscopy and the X-ray diffraction. The results indicated that ZnO nanostructure formed mainly along the crystal orientation [002] on silicon substrate at moderate temperatures. The crystallization was improved by prolonging growth time and the morphologies mainly depended on the distribution of the growth temperature. The growth process was attributed to vapor-liquid-solid mechanism.
APPLICATION OF ENTANGLED STATE IN QUANTIZING SUPERCONDUCTING CAPACITOR MODEL IN THE PRESENCE OF A VOLTAGE BIAS AND A CURRENT BIAS
Authors: FAN HONG-YI
Published: March 2004

Based on the entangled state representation and the appropriate bosonic phase operator we develop the superconducting capacitor model in the presence of a voltage bias and a current bias. In so doing, the full Hamiltonian operator theory for a superconducting barrier is established.
BIOLOGICAL DELAY SYSTEMS AND THE MIKHAILOV CRITERION OF STABILITY
Authors: FORYŚ URSZULA
Published: March 2004

This paper deals with the stability analysis of biological delay systems. The Mikhailov criterion of stability is presented (and proved in the Appendix) for the case of discrete delay and distributed delay (i.e., delay in integral form). This criterion is used to check stability regions for some well-known equations, especially for the delay logistic equation and other equations with one discrete delay which appear in many applications. Some illustrations of the behavior of Mikhailov hodograph are shown.
STABILITY ANALYSIS OF A PREY-PREDATOR MODEL WITH DELAY AND HARVESTING
Authors: KAR TAPAN KUMAR
Published: March 2004

An analysis is presented for a model of a two species prey-predator system subject to the combined effects of delay and harvesting. Our study shows that, both the delay and harvesting effort may play a significant role on the stability of the system. Computer simulations are carried out to explain some of the mathematical conclusions.
A MODEL FOR OPTIMAL CHEMICAL CONTROL OF LEAF AREA DAMAGED BY FUNGI POPULATION — PARAMETER DEPENDENCE
Authors: OLIVEIRA R. Z. G. , BASSANEZI R. C. , YANG H. M. , ADAMI A.
Published: March 2004

We present a model to study a fungi population submitted to chemical control, incorporating the fungicide application directly into the model. From that, we obtain an optimal control strategy that minimizes both the fungicide application (cost) and leaf area damaged by fungi population during the interval between the moment when the disease is detected (t=0) and the time of harvest (t=tf). Initially, the parameters of the model are considered constant. Later, we consider the apparent infection rate depending on the time (and the temperature) and do some simulations to illustrate and to compare with the constant case.
COORDINATION AND COLLABORATION ACTIVITIES IN COOPERATIVE INFORMATION SYSTEMS
Authors: OMICINI ANDREA , OSSOWSKI SASCHA
Published: March 2004

The notions of coordination, collaboration and cooperation have originated a number of heterogeneous research lines in diverse scientific areas, both inside and outside Computer Science — along with a number of different acceptations for the terms as well. The basic and almost obvious correlation between these terms, however, has not yet led to a satisfactory scientific overall picture that could put them in the right perspective, emphasizing their commonalities and distinctions. Still, there is a great potential for cross-fertilization between the different strands of work. In particular, if the mutual relationship between these terms was understood and commonly accepted, it would be much easier to adapt and apply many innovative ideas developed by the different communities to the field of cooperative information systems. In this article, we outline a possible unified conceptual framework, by suitably re-interpreting findings from Activity Theory. There, a clear definition for both coordination and cooperation as collaborative activities can be found and used as a reference, which is centred around the notion of (coordination) artifact. Then, we gladly introduce four contributions, selected from the best papers of the 18th ACM Symposium on Applied Computing and suitably revised for the International Journal on Cooperative Information Systems, that show how some of the most recent results of the research on coordination can be fruitfully exploited and applied to the field of cooperative information systems.
A SOFTWARE ENGINEERING APPROACH FOR COORDINATION POLICIES ELICITATION
Authors: MUCCINI HENRY , MANCINELLI FABIO
Published: March 2004

In a software system, software processes can be concurrently run by system actors (e.g. agents, components), by making use of shared or dedicated software resources. Coordination is a research area oriented to understand, explicitly model and analyze how activities can depend on each other, in a concurrent system. Many coordination models and languages have been presented in the last few years in order to make coordination a first class entity in the development of a software system. However, what usually happens, is that coordination is described late in the software development and it is not integrated in a typical software process. What we claim, with our research, is that if coordination becomes explicit and formalized as soon as possible in the software life cycle, then it is possible to create coordination-aware software systems, which are easily maintained and developed. What we present, in the following, is a software engineering view of coordination. Diagrams produced during a UML-based software modeling, are analyzed in order to help a software engineer in the difficult task to elicit coordination requirements from informal ones. We show how UML models can drive an elicitation process in order to identify coordination requirements, and can graphically describe which elements need coordination.
RING THEORETIC PROPERTIES OF QUANTUM GRASSMANNIANS
Authors: KELLY A. C. , LENAGAN T. H. , RIGAL L.
Published: March 2004

The m×n quantum grassmannian, [Formula: see text], with m≤n, is the subalgebra of the algebra [Formula: see text] of quantum m×n matrices that is generated by the maximal m×m quantum minors. Several properties of [Formula: see text] are established. In particular, a k-basis of [Formula: see text] is obtained, and it is shown that [Formula: see text] is a noetherian domain of Gelfand–Kirillov dimension m(n-m)+1. The algebra [Formula: see text] is identified as the subalgebra of coinvariants of a natural left coaction of [Formula: see text] on [Formula: see text] and it is shown that [Formula: see text] is a maximal order.
MOORE–PENROSE LOCALIZATION
Authors: ÁNH PHAM NGOC , MÁRKI LÁSZLÓ
Published: March 2004

For rings with involution, we describe the close interrelation between localizations with respect to group inverses and Moore–Penrose inverses, respectively. In full generality, we show that Moore–Penrose localizations are equivalent with certain Fountain–Gould localizations, and that "full" Moore–Penrose and Fountain–Gould orders, respectively, coincide in a perfect or strongly regular ring.
COORDINATE SETS OF GENERALIZED GALOIS RINGS
Authors: GONZÁLEZ S. , MARTÍNEZ C. , RÚA I. F. , MARKOV V. T. , NECHAEV A. A.
Published: March 2004

A Generalized Galois Ring (GGR) S is a finite nonassociative ring with identity of characteristic pn, for some prime number p, such that its top-factor [Formula: see text] is a semifield. It is well-known that if S is an associative Galois Ring (GR), then it contains a multiplicatively closed subset isomorphic to [Formula: see text], the so-called Teichmüller Coordinate Set (TCS). In this paper we show that the existence of a TCS characterizes GR in the class of all GGR S such that the multiplicative loop [Formula: see text] is right (or left) primitive.
ENDOMORPHISM ALGEBRAS OF PROJECTIVE MODULES OVER LAURA ALGEBRAS
Authors: ASSEM IBRAHIM , COELHO FLÁVIO U.
Published: March 2004

Let A be a connected artin algebra, and e be an idempotent in A such that B=eAe is connected. We show here that if A is laura, left (or right) glued or weakly shod, so is B, respectively. Our proof yields also similar (and known) results for shod and quasi-tilted algebras.
ON THE FINITE TYPE OF FAMILIES OF INDECOMPOSABLE MODULES
Authors: DUNG NGUYEN VIET
Published: March 2004

We show that a family [Formula: see text] of indecomposable modules has only a finite number of non-isomorphic members if [Formula: see text] satisfies either of the following: (a) [Formula: see text] has a preinjective partition, and satisfies the artinian condition on morphisms between the Mi; (b) [Formula: see text] has a preprojective partition, and satisfies the noetherian condition on morphisms between the Mi. As a consequence, we recover some of recent results due to B. Huisgen-Zimmermann and M. Saorín [11], establishing the relationships between the endo-structure of infinite direct sums ⊕i∈IMi of indecomposable modules Mi and the finiteness of isomorphism classes of the Mi.
THE VAN EST SPECTRAL SEQUENCE FOR HOPF ALGEBRAS
Authors: BEGGS E. J. , BRZEZIŃSKI TOMASZ
Published: March 2004

Various aspects of the de Rham cohomology of Hopf algebras are discussed. In particular, it is shown that the de Rham cohomology of an algebra with the differentiable coaction of a cosemisimple Hopf algebra with trivial 0-th cohomology group, reduces to the de Rham cohomology of (co)invariant forms. Spectral sequences are discussed and the van Est spectral sequence for Hopf algebras is introduced. A definition of Hopf–Lie algebra cohomology is also given.
TOPOLOGICAL STRINGS ON NONCOMMUTATIVE MANIFOLDS
Authors: KAPUSTIN ANTON
Published: March 2004

We identify a deformation of the N=2 supersymmetric sigma model on a Calabi–Yau manifold X which has the same effect on B-branes as a noncommutative deformation of X. We show that for hyperkähler X such deformations allow one to interpolate continuously between the A-model and the B-model. For generic values of the noncommutativity and the B-field, properties of the topologically twisted sigma-models can be described in terms of generalized complex structures introduced by N. Hitchin. For example, we show that the path integral for the deformed sigma-model is localized on generalized holomorphic maps, whereas for the A-model and the B-model it is localized on holomorphic and constant maps, respectively. The geometry of topological D-branes is also best described using generalized complex structures. We also derive a constraint on the Chern character of topological D-branes, which includes A-branes and B-branes as special cases.
CONFORMALLY OSSERMAN MANIFOLDS AND CONFORMALLY COMPLEX SPACE FORMS
Authors: BLAŽIĆ N. , GILKEY P.
Published: March 2004

We characterize manifolds which are locally conformally equivalent to either complex projective space or to its negative curvature dual in terms of their Weyl curvature tensor. As a byproduct of this investigation, we classify the conformally complex space forms if the dimension is at least 8. We also study when the Jacobi operator associated to the Weyl conformal curvature tensor of a Riemannian manifold has constant eigenvalues on the bundle of unit tangent vectors and classify such manifolds which are not conformally flat in dimensions congruent to 2 mod 4.
REGULARIZED CALCULUS: AN APPLICATION OF ZETA REGULARIZATION TO INFINITE DIMENSIONAL GEOMETRY AND ANALYSIS
Authors: AKIRA ASADA
Published: March 2004

A method of regularization in infinite dimensional calculus, based on spectral zeta function and zeta regularization is proposed. As applications, a mathematical justification of appearance of Ray–Singer determinant in Gaussian Path integral, regularized volume form of the sphere of a Hilbert space with the determinant bundle, eigenvalue problems of regularized Laplacian, are investigated. Geometric counterparts of regularization procedure are also discussed applying arguments from noncommutative geometry.
EVOLUTIONARY OPTIMIZATION (EvOpt): A BRIEF REVIEW AND ANALYSIS
Authors: SARKER RUHUL , KAMRUZZAMAN JOARDER , NEWTON CHARLES
Published: March 2004

Evolutionary Computation (EC) has attracted increasing attention in recent years, as powerful computational techniques, for solving many complex real-world problems. The Operations Research (OR)/Optimization community is divided on the acceptability of these techniques. One group accepts these techniques as potential heuristics for solving complex problems and the other rejects them on the basis of their weak mathematical foundations. In this paper, we discuss the reasons for using EC in optimization. A brief review of Evolutionary Algorithms (EAs) and their applications is provided. We also investigate the use of EAs for solving a two-stage transportation problem by designing a new algorithm. The computational results are analyzed and compared with conventional optimization techniques.
EVOLUTIONARY NETWORK DESIGN: HYBRID GENETIC ALGORITHMS APPROACH
Authors: GEN MITSUO , CHENG RUNWEI
Published: March 2004

In recent years we have evidenced an extensive effort in the development of computer communication networks, which have deeply integrated in human being's everyday life. One of the important aspects of the network design process is the topological design problem involved in establishing a communication network. However, with the increase of the problem scale, the conventional techniques are facing the challenge to effectively and efficiently solve those complicated network design problems.

In this article, we give a brief survey on our recent research works of network design problems by using genetic algorithms (GAs), such as, multistage process planning problem, fixed charge transportation problem, minimum spanning tree problem, centralized network design, and local area network design, shortest path problem, minimum cost maximum flow problem, and optimal scheduling problems based on network topology. All these problems are illustrated from the point of genetic representation encoding skill and the genetic operators with hybrid strategies. Numerical experiments show the effectiveness and efficiency of such kind of GA-based approach.
AN ASYNCHRONOUS PARALLEL EVOLUTION STRATEGY
Authors: RUNARSSON THOMAS PHILIP
Published: March 2004

This work introduces a new asynchronous parallel self-adaptive evolution strategy. An asynchronous scheme is chosen because the load on the processors is usually unbalanced. The proposed algorithm is non-blocking leaving no processor idle at any given time. The motivation and theory for the algorithm is based on the author's previous analysis of continuous evolution strategies9 and the reduction of random fluctuation in mutative self-adaptation.7 The algorithm is implemented in C ++ using Posix threads and tested on a number of unimodal and multimodal benchmark problems. The result is an efficient and effective numerical optimization strategy for multi-processor machines.
SCHEDULING FLEXIBLE JOB-SHOPS: A WORST CASE ANALYSIS AND AN EVOLUTIONARY ALGORITHM
Authors: KACEM IMED
Published: March 2004

In this paper, we deal with the flexible job shop scheduling problem. We propose an efficient heuristic method for solving the assignment problem. Indeed, we propose a worst case analysis to evaluate the performance of such a heuristic. The second specificity of the problem studied is the sequencing property. Our approach consists in the application of an evolutionary algorithm based on a set of adapted operators to solve the sequencing step. Some lower bounds for the problem (previously proposed in Ref. 1) will be used in order to evaluate the quality of our method and the solutions according to the different criteria.
Starting at the Beginning: New Perspectives on the Biology of Mucosal T Cells
Authors: Cheroutre Hilde
Published: March 2004

The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism. This dilemma imposed by the gut environment has probably contributed significantly to the evolutionary drive that has led to sophisticated mechanisms and diversification of the immune system to allow for protection while maintaining the integrity of the mucosal barrier. The immense expansion and specialization of the immune system is particularly mirrored in the phylogeny, ontogeny, organization, and regulation of the adaptive intraepithelial lymphocytes, or IEL, which are key players in the unique intestinal defense mechanisms that have evolved in mammals.
CD40/CD154 Interactions at the Interface of Tolerance and Immunity
Authors: Quezada Sergio A. , Jarvinen Lamis Z. , Lind Evan F. , Noelle Randolph J.
Published: March 2004

Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that αCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of αCD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.
Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells
Authors: Geijtenbeek Teunis B.H. , van Vliet Sandra J. , Engering Anneke , 't Hart Bert A. , van Kooyk Yvette
Published: March 2004

▪ Abstract  Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naïve T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.
Interleukin-10andRelatedCytokines andReceptors
Authors: Pestka Sidney , Krause Christopher D. , Sarkar Devanand , Walter Mark R. , Shi Yufang , Fisher Paul B.
Published: March 2004

▪ Abstract  The Class 2 α-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-α, -β, -ɛ, -κ, -ω, -δ, -τ, and -γ) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.
Drosophila: The Genetics of Innate Immune Recognition and Response
Authors: Brennan Catherine A. , Anderson Kathryn V.
Published: March 2004

▪ Abstract  Because of the evolutionary conservation of innate mechanisms of host defense, Drosophila has emerged as an ideal animal in which to study the genetic control of immune recognition and responses. The discovery that the Toll pathway is required for defense against fungal infection in Drosophila was pivotal in studies of both mammalian and Drosophila immunity. Subsequent genetic screens in Drosophila to isolate additional mutants unable to induce humoral responses to infection have identified and ordered the function of components of two signaling cascades, the Toll and Imd pathways, that activate responses to infection. Drosophila blood cells also contribute to host defense through phagocytosis and signaling, and may carry out a form of self-nonself recognition that is independent of microbial pattern recognition. Recent work suggests that Drosophila will be a useful model for dissecting virulence mechanisms of several medically important pathogens.
Immunity toTuberculosis
Authors: North Robert J. , Jung Yu-Jin
Published: March 2004

▪ Abstract  Only 5 to 10% of immunocompetent humans are susceptible to tuberculosis, and over 85% of them develop the disease exclusively in the lungs. Human immunodeficiency virus (HIV)-infected humans, in contrast, can develop systemic disease that is more quickly lethal. This is in keeping with other evidence showing that susceptible humans generate some level of Th1 immunity to Mycobacterium tuberculosis (Mtb) infection. Tuberculosis in mice is also exclusively a lung disease that is progressive and lethal, in spite of the generation of Th1-mediated immunity. Thus mouse tuberculosis is a model of tuberculosis in susceptible humans, as is tuberculosis in guinea pigs and rabbits. Inability to resolve infection and prevent disease may not be a consequence of the generation of an inadequate number of Th1 cells but of an intrinsic deficiency in macrophage function that prevents these cells from expressing immunity. If this proves to be true, vaccinating susceptible humans against tuberculosis will be a difficult task.
Autoimmune and Inflammatory Mechanisms in Atherosclerosis
Authors: Wick Georg , Knoflach Michael , Xu Qingbo
Published: March 2004

The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.
RAGs andRegulation ofAutoantibodies
Authors: Jankovic Mila , Casellas Rafael , Yannoutsos Nikos , Wardemann Hedda , Nussenzweig Michel C.
Published: March 2004

▪ Abstract  Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process.
Phosphoinositide3-Kinase: Diverse Roles in Immune Cell Activation
Authors: Deane Jonathan A. , Fruman David A.
Published: March 2004

▪ Abstract  Cells of the immune system carry out diverse functions that are controlled by surface receptors for antigen, costimulatory molecules, cytokines, chemokines, and other ligands. A shared feature of signal transduction downstream of most receptors on immune cells, as in nonhematopoietic cell types, is the activation of phosphoinositide 3-kinase (PI3K). The mechanism by which this common signaling event is elicited by distinct receptors and contributes to unique functional outcomes is an intriguing puzzle. Understanding how specificity is achieved in PI3K signaling is of particular significance because altered regulation of this pathway is observed in many disease states, including leukemia and lymphoma. Here we review recent advances in the understanding of PI3K signaling mechanisms in different immune cells and receptor systems. We emphasize the concept that PI3K and its products are components of complex networks of interacting proteins and second messengers, rather than simple links in linear signaling cascades.
The BCR-ABL Story: Bench to Bedside and Back
Authors: Wong Stephane , Witte Owen N.
Published: March 2004

The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.
Transcriptional Control of Early B Cell Development
Authors: Busslinger Meinrad
Published: March 2004

The generation of B-lymphocytes from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental aspects. Ikaros and PU.1 act in parallel pathways to control the development of lymphoid progenitors in part by regulating the expression of essential signaling receptors (Flt3, c-Kit, and IL-7Rα). The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis. Pax5 restricts the developmental options of lymphoid progenitors to the B cell lineage by repressing the transcription of lineage-inappropriate genes and simultaneously activating the expression of B-lymphoid signaling molecules. LEF1 and Sox4 contribute to the survival and proliferation of pro-B cells in response to extracellular signals. Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements.
Association Studies in Candidate Genes: Strategies to Select SNPs to Be Tested
Authors: Cousin E. , Genin E. , Mace S. , Ricard S. , Chansac C. , del Zompo M. , Deleuze J.F.
Published: March 2004

Objective: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. Method: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. Results: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.
Reconsidering the Role of Overcoming Perturbations in Cognitive Development: Constructivism and Consciousness
Authors: Becker Joe
Published: March 2004

Constructivist theory must choose between the hypothesis that felt perturbation drives cognitive development (the priority of felt perturbation) and the hypothesis that the particular process that eventually produces new cognitive structures first produces felt perturbation (the continuity of process). There is ambivalence in Piagetian theory regarding this choice. The prevalent account of constructivist theory adopts the priority of felt perturbation. However, on occasion Piaget has explicitly rejected it, simultaneously endorsing the continuity of process. First, I explicate and support this latter position, arguing that felt perturbation emerges after the construction of a new cognitive structure has already begun. Next, I discuss the broader significance of rejecting the priority of felt perturbation in terms of a distinction between two types of theory of effective change, labeled Lamarckian and Darwinian in analogy with familiar theories of evolutionary change. Rejecting the priority of felt perturbation allows the development of a Darwinian perspective. In turn, the Darwinian perspective offers advantages for elaborating the analogy Piaget proposed between consciousness and the relation of form and content.
Gemcitabine plus Paclitaxel as First-Line Chemotherapy for Patients with Advanced Breast Cancer
Authors: Delfino Carlos , Caccia Graciela , Gonzáles Luis Riva , Mickiewicz Elizabeth , Rodger Jeannette , Balbiani Luis , Morales Daniel Flores , Comba Alberto Zori , Brosio Celia
Published: March 2004

Objectives: To assess the efficacy and tolerability of gemcitabine and paclitaxel as first-line treatment in advanced breast cancer. Methods: Patients with histologically confirmed metastatic or metastatic plus locally advanced breast cancer received gemcitabine 1,200 mg/m2 on days 1 and 8 and paclitaxel 175 mg/m2 on day 1 every 21 days for 8 cycles. Results: From December 1999 to August 2001, 45 patients, with a median age of 53.5 years (range, 22–77), received a total of 260 cycles. All were assessable for response and toxicity. Twenty-seven patients had prior adjuvant therapy. Hormonal receptor status was positive in 31.1% and negative in 40.0% of patients. Main metastatic sites included soft tissue (62.2%) and lung (53.3%). The objective response rate was 66.7%; complete response, 22.2%; partial response, 44.4%; stable disease, 15.6%; progressive disease, 17.8%. Median duration of response was 18 months and median time to tumor progression was 11 months. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia developed in 13.3% of patients, and 15.5% developed grade 3/4 mucositis. No treatment-related deaths occurred. Median overall survival was 19 months. Conclusion: Gemcitabine plus paclitaxel is an active combination with a favorable toxicity profile as first-line treatment for patients with advanced breast cancer.
Transcatheter Arterial Chemotherapy with and without Embolization in Patients with Hepatocellular Carcinoma
Authors: Ikeda Masafumi , Maeda Seishi , Shibata Junji , Muta Ryushi , Ashihara Hiroshi , Tanaka Motohiko , Fujiyama Shigetoshi , Tomita Kimio
Published: March 2004

Objective: This study compared the antitumor effect, adverse effects and survival between transcatheter arterial embolization (TAE) and transcatheter arterial infusion chemotherapy (TAI) in patients with hepatocellular carcinoma (HCC). Methods: The study population consisted of 168 consecutive patients with advanced HCC treated with transcatheter arterial treatments using cisplatin suspended in lipiodol. Among these, 74 patients were treated with TAE, and the remaining 94 patients were treated with TAI. Results: There were no significant differences in any baseline characteristics except hemoglobin, platelets, albumin, and glutamic pyruvic transaminase. Complete or partial tumor response was achieved in 54 patients (73%) in the TAE group and in 48 patients (51%) in the TAI group (p < 0.01). There were two treatment-related deaths caused by acute hepatic failure and acute renal failure in the TAE group. Nausea and deterioration of serum transaminase after TAE were significantly more severe than after TAI. Median survival time and survival rates at 5 years were 3.1 years and 25% in the TAE group, and 2.5 years and 18% in the TAI group (p = 0.37). Conclusion: TAE has a higher antitumor effect than TAI, but does not significantly improve the survival of patients with HCC.
Phase II Study of Gemcitabine Combined with Uracil-Tegafur in Metastatic Pancreatic Cancer
Authors: Lee Jeeyun , Park Joon Oh , Kim Won Seog , Lee Soon Il , Song Seo Young , Lim Do Hoon , Choi Seong-Ho , Heo Jin-Seok , Lee Kyu Taek , Lee Jong Kyun , Heo Jin-Seok , Kim Kihyun , Jung Chul Won , Im Young-Hyuck , Lee Mark H. , Kang Won Ki , Park Keunchil
Published: March 2004

Objective: The single agent gemcitabine is the standard first-line treatment for advanced pancreatic cancer. Recent studies of a combination of gemcitabine and 5-fluorouracil (5-FU) revealed that survival data were superior to those with gemcitabine or 5-FU alone. The administration of oral uracil-tegafur (UFT) is more convenient and simulates the effect of a continuous or protracted infusion of 5-FU. Therefore, we conducted a phase II study of gemcitabine combined with UFT in metastatic pancreatic cancer patients and assessed the efficacy and the toxicity of the regimen. Methods: Twenty-two pancreatic adenocarcinoma patients (18 males, 4 females) were enrolled from December 2000 to September 2002. The regimen consisted of gemcitabine 1,000 mg/m2 once weekly for 3 consecutive weeks, and oral UFT 390 mg/m2/day (in 3 divided doses) on days 1–14. The cycle was repeated every 28 days. The objective tumor response was evaluated after 2 courses of chemotherapy. Results: 82 cycles were administered in total, with a median of 3 cycles per patient (range 1–6 cycles). The median age was 52 years (range 28–69 years). Response to treatment could be assessed in all patients. The objective response rate was 22.7% (95% CI, 7.8–45.4) with no complete response and 5 partial responses. Four patients (18.2%) had stable disease and 13 patients (59.1%) had a progression. The median time to progression was 4.2 months (range 0.9–13.6). The median overall survival was 5.8 months (range 0.5–13.6). Of 10 patients eligible for the assessment of clinical benefit response, 4 (40%, 95% CI 12.2–73.8) showed clinical benefit. Among 21 patients with baseline CA 19-9 levels, CA 19-9 was reduced by 50% or more in 12 patients (57.1%). The chemotherapy was generally well tolerated and the most common grade 3–4 toxic side effects were neutropenia (18.2%), anemia (4.5%), and diarrhea (4.5%). Conclusion: The combination chemotherapy with gemcitabine and UFT in metastatic pancreatic cancer was tolerable for most patients but showed modest response rates and clinical benefit. However, a randomized phase III study should be conducted in order to further test the efficacy of the regimen.
A Phase II Study of Three-Weekly Docetaxel and Weekly Trastuzumab in HER2-Overexpressing Advanced Breast Cancer
Authors: Montemurro Filippo , Choa Gabriella , Faggiuolo Roberto , Donadio Michela , Minischetti Monica , Durando Antonio , Capaldi Antonio , Vietti-Ramus Guido , Alabiso Oscar , Aglietta Massimo
Published: March 2004

Background: To test safety and activity of 3-weekly doses of docetaxel and a weekly dose of trastuzumab in women with HER2-overexpressing advanced breast cancer. Patients and Methods: Forty-two women, median age 53 years (range 36–73 years), with HER2-overexpressing advanced breast cancer were enrolled in a study of docetaxel, 75 mg/m2 q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose, 2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic involvement. Thirty-five patients had received prior chemotherapy as part of their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty-one patients had been previously exposed to an anthracycline and 11 to paclitaxel. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplant. Results: 226 cycles (median 6, range 1–6) were administered. The median delivered dose intensity for docetaxel was 24 mg/m2/week (range 16–25 mg/m2/week). The intent to treat overall response rate was 67% (95% confidence interval, 52–79%). Median progression-free survival, time to treatment failure, and duration of response were 9, 8 and 12 months, respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The most common grade 3/4 toxicity was neutropenia (76% of the patients), although febrile neutropenia did not occur. Conclusions: Three-weekly doses of docetaxel and a weekly dose of trastuzumab is an active and safe combination in patients with HER2-overexpressing advanced breast cancer.