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It was long known from the work of Chiller and Weigle, in the 1970s [1], that deaggregated (monomeric) foreign immunoglobulins were poorly immunogenic, and capable of inducing tolerance. Aggregated immunoglobulins were, in contrast, very immunogenic. [ABSTRACT FROM AUTHOR]

The subcapsular region of the kidney has frequently served as the site of choice for transplantation studies owing to a number of compelling reasons. High levels of vascularization provide a ready blood supply, whereas the subcapsular region itself can accommodate tissues of a range of size and sources. Historically, transplantation to this site has proven important for studies of both central and peripheral tolerance. Here, the transplantation technique and its major variations are described for broad application. [ABSTRACT FROM AUTHOR]

Investigations into the mechanisms of immunological tolerance are currently hindered by a paucity of convenient markers, both for the identification and isolation of tolerant cell types and for monitoring the establishment of tolerance in in vivo models. Although high-affinity autoreactive T cells are deleted in the thymus during the establishment of central tolerance, escaping autoreactive cells require modulation in the periphery. Dendritic cells (DC) and regulatory T cells (Treg) are both implicated in the establishment and maintenance of peripheral tolerance, although specific interactions and mechanisms remain to be established. The serial analysis of gene expression (SAGE) approach to transcript profiling offers potential, not only for new insight into tolerogenic mechanisms, unbiased by current dogma, but also for the identification of novel molecular markers of tolerance. SAGE provides both quantitative and qualitative information on transcripts sampled on the basis of frequency of occurrence in the initial mRNA pool. This information is generated in the form of electronic databases that accumulate as a permanent resource and confer on SAGE the ability to readily compare across wide datasets. This offers particular potential when attempting to correlate gene expression with functional phenotype. By comparing variously generated functionally distinct/related immune populations, such as effector T cells and either natural, CD4+CD25+, or adaptive, Tr1, Tregs and/or immune and tolerance prone DC, it should be possible, using SAGE, to identify both individual genes and also signatures of genes associated with protolerogenic rather than immunogenic phenotypes. [ABSTRACT FROM AUTHOR]

Recent years have witnessed a progressive acceptance of the dual role played by dendritic cells (DC) in the initiation of immune responses and their specific attenuation through the induction of immunological tolerance. Nevertheless, as terminally differentiated cells of the myeloid lineage, DC share with macrophages an inherent resistance to genetic modification, greatly restricting strategies available for studying their physiology and function. Consequently, little is known of the molecular interactions provided by DC that underlie the critical decision between tolerance and immunity. Embryonic stem (ES) cells are, by contrast, relatively amenable to genetic modification. Furthermore, their propensity for self-renewal, one of the cardinal features of a stem cell, permits cloning at the single cell level and the rational design of ES cell lines, uniformly expressing a desired, mutant phenotype. Here, we describe how another defining property of ES cells, their demonstrable pluripotency, may be harnessed for their directed differentiation along the DC pathway, enabling the generation of limitless numbers of DC faithfully expressing candidate genes of interest. The protocols we outline in this chapter may, therefore, offer new opportunities for dissecting the biology of DC and the molecular basis of their unique properties. [ABSTRACT FROM AUTHOR]

Tolerance induction induced by monoclonal antibodies or co-receptor blockade is robust enough to resist breakdown by adoptive transfer of lymphocytes. Such resistance, the hallmark of dominant tolerance, is mediated by CD4 + regulatory T cells. CD4 + CD25 + T cells inhibit lymphopenia-mediated accumulation of T cells in vivo, but caution should be exerted when investigating antigen-specific regulation in replete mice. A number of different deletional and tolerogenic processes following antibody-induced tolerance are discussed in this chapter, including activation-induced cell death, immunosuppressive cytokines, and immunopriveleged sites. The possibility of spreading tolerance to other cells, including parenchymal cells, is also discussed. This chapter emphasizes recent evidence that shows that self-tolerance does not rely on several mechanisms running independently, but rather a continuum of synergistic and overlapping mechanisms. [ABSTRACT FROM AUTHOR]

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The majority of all proteins are modularly built from a limited set of approximately 1,000 structural domains. The knowledge of a common protein fold topology in the ligand-sensing cores of protein domains can be exploited for the design of small-molecule libraries in the development of inhibitors and ligands. Thus, a novel strategy of clustering protein domain cores based exclusively on structure similarity considerations (protein structure similarity clustering, PSSC) has been successfully applied to the development of small-molecule inhibitors of acetylcholinesterase and the 11β-hydroxysteroid dehydrogenases based on the structure of a naturally occurring Cdc25 inhibitor. The efficiency of making use of the scaffolds of natural products as biologically prevalidated starting points for the design of compound libraries is further highlighted by the development of benzopyran-based FXR ligands. [ABSTRACT FROM AUTHOR]

The clause linking technique of Lee and Plaisted proves the unsatisfiability of a set of first-order clauses by generating a sufficiently large set of instances of these clauses that can be shown to be propositionally unsatisfiable. In recent years, this approach has been refined in several directions, leading to both tableau-based methods, such as the Disconnection Tableau Calculus, and saturation-based methods, such as Primal Partial Instantiation and Resolution-based Instance Generation. We investigate the relationship between these calculi and answer the question to what extent refutation or consistency proofs in one calculus can be simulated in another one. [ABSTRACT FROM AUTHOR]

Due to the fact that the biometric characteristics of a person are bound to that person, biometric methods deployed for signer authentication have the potential of improving the binding of electronic signatures to persons. If there is evi dence that a biometric method was used for signer authentication, and if the level of security of this method is suffi ciently high, then the receiver of a signed docu ment can trust that the signature creation was indeed initiated by the legitimate holder of the private signature key. To achieve this goal, an approach to provide evidence of the use of biometric signer authentication has been developed. The approach has been implemented in a prototype electronic signature creation system with fingerprint verification. [ABSTRACT FROM AUTHOR]

We present a new method for proving termination of term rewriting systems automatically. It is a generalization of the match bound method for string rewriting. To prove that a term rewriting system terminates on a given regular language of terms, we first construct an enriched system over a new signature that simulates the original derivations. The enriched system is an infinite system over an infinite signature, but it is locally terminating: every restriction of the enriched system to a finite signature is terminating. We then construct iteratively a finite tree automaton that accepts the enriched given regular language and is closed under rewriting modulo the enriched system. If this procedure stops, then the enriched system is compact: every enriched derivation involves only a finite signature. Therefore, the original system terminates. We present three methods to construct the enrichment: top heights, roof heights, and match heights. Top and roof heights work for left-linear systems, while match heights give a powerful method for linear systems. For linear systems, the method is strengthened further by a forward closure construction. Using these methods, we give examples for automated termination proofs that cannot be obtained by standard methods. [ABSTRACT FROM AUTHOR]

This chapter describes general methodologies for the synthesis of lipidated, that is, prenylated and/or palmitoylated peptides. Standard operating procedures are given for peptide synthesis both on the polymeric support and in solution. [ABSTRACT FROM AUTHOR]

Over the last few decades, the use of swine as an animal model for human diseases in biomedical research has been steadily increasing because of similarities between the two species. The gnotobiotechnique, on the other hand, has been developed further since the beginning of the 20th century (1-3), stimulated by the need for an experimental model to study bacteria-host interactions in sterile laboratory animals, during the course of an infection with a defined pathogen. The combination of both aspects led to the development of a complex isolator system that made the delivery of piglets by cesarean section and their rearing in a self-contained unit possible, shielded from undesirable contaminating germs (4,5). In such a microbiologically well-defined environment, pathogen-host interactions can be studied without the influence of accompanying bacterial flora. [ABSTRACT FROM AUTHOR]

In 1890 it was shown that resistance to diphtheria toxin could be transferred from one animal to another by transfer of serum (1). From this discovery, passive antibody therapy was developed as an effective treatment for infectious diseases and for neutralization of toxins, and continues to be used to this day. Meanwhile, there have been continued efforts to use antibodies for cancer therapy, starting with the pioneering work of Hericourt and Richet in 1895 (2), which was the forerunner of the "magic bullet" concept. However, all of the early work on tumor therapy led ultimately to disappointment (3). The problems were readily acknowledged, i.e., lack of specificity and reproducibility, lack of purity, and the xenogeneic immune response. Developments over the past 20 years, as described throughout this book, have effectively overcome all of these technical problems, often in very ingenious ways. The difficulty we have now is different. There are just too many potential new antibody-based treatments for them all to be properly evaluated in the clinic. Many will still fail because of factors that are hard to predict from experiments: unexpected toxicity, biological heterogeneity of the target disease, or lack of access to the appropriate tissue. [ABSTRACT FROM AUTHOR]

Prospects for the Application of Antibodies in Medicine [ABSTRACT FROM AUTHOR]

In divisible torsion-free abelian groups, the efficiency of the cancellative superposition calculus can be greatly increased by combining it with a variable elimination algorithm that transforms every clause into an equivalent clause without unshielded variables. We show that the resulting calculus is not only refutationally complete (even in the presence of arbitrary free function symbols), but that it is also a decision procedure for the theory of divisible torsion-free abelian groups. [ABSTRACT FROM AUTHOR]

Variable overlaps are one of the main sources for the inefficiency of AC or ACU theorem proving calculi. In the presence of the axioms of abelian groups or at least cancellative abelian monoids, ordering restrictions allow us to avoid some of these overlaps, but inferences with unshielded variables remain necessary. In divisible torsion-free abelian groups, for instance the rational numbers, every clause can be transformed into an equivalent clause without unshielded variables. We show how such a variable elimination algorithm can be integrated into the cancellative superposition calculus. The resulting calculus is refutationally complete with respect to the axioms of divisible torsion-free abelian groups and allows us to dispense with variable overlaps altogether. If abstractions are performed eagerly, the calculus makes it furthermore possible to avoid the computation of AC unifiers and AC orderings. [ABSTRACT FROM AUTHOR]

The combinator S has the reduction rule Sx y z → x z (y z). We investigate properties of ground terms built from S alone. We show that it is decidable whether such an S-term has a normal form. The decision procedure makes use of rational tree languages. We also exemplify and summarize other properties of S-terms and hint at open questions. [ABSTRACT FROM AUTHOR]

This article focuses on the role of the terrorist organization ETA in politics in Basque, Spain. In the era of Franco dictatorship, ETA was considered as a vindicator of the honor of Basque people. Thanks to the organization, the resoluteness of opposition by the minority has renewed strength and eloquence, as manifested by strikes that took place in the region. However, in the late 1980, the growing dissociation of large groups of the population from the organization set in. The reasons are the obvious brutality and inhumanity of ETA actions. Many saw that the organization has become dangerous terrorists murdering innocent people, from freedom fighters before. Thus, the Spanish government took measures to control and deprive ETA of its power. Some members were deported or extradited to third countries while others are placed in detention cells.