Non-caspase proteases: triggers or amplifiers of apoptosis?

Caspases are the most important effectors of apoptosis, the major form of programmed cell death (PCD) in multicellular organisms. This is best reflected by the appearance of serious development defects in mice deficient for caspase-8, -9, and -3. Meanwhile, caspase-independent PCD, mediated by other proteases or signaling components has been described in numerous publications. Although we do not doubt that such cell death exists, we propose that it has evolved later during evolution and is most likely not designed to execute, but to amplify and speed-up caspase-dependent cell death. This review shall provide evidence for such a concept.     

γδ T-APCs: a novel tool for immunotherapy?

The series of seminal articles in this book clearly illustrate the multi-functional nature of γδ T cells. Some of the functions correlate with the tissue tropism of distinct γδ T cell subsets whereas others appear to result from oligoclonal selection. Here, we discuss the antigen-presenting cell (APC) function of the major subset of circulating γδ T cells, Vγ9/Vδ2 T cells, present in human blood. During tissue culture, Vγ9/Vδ2 T cells uniformly respond to a class of non-peptide antigens, so-called prenyl pyrophosphates, derived from stressed host cells or from microbes. It is this feature that distinguishes human (and primate) Vγ9/Vδ2 T cells from αβ and γδ T cells of all other species and that forms the basis for detailed studies of human Vγ9/Vδ2 T cells. One of the consequences of Vγ9/Vδ2 T cell activation is the rapid acquisition of APC characteristics (γδ T-APCs) reminiscent of mature dendritic cells (DCs). In the following discussion, we will discriminate between the potential use of γδ T-APCs as a cellular vaccine in immunotherapy and their role in anti-microbial immunity. Exploiting the APC function in γδ T-APCs represents a true novelty in current immunotherapy research and may lead to effective, anti-tumor immunity in cancer patients.     

Formation of the B cell synapse: retention or recruitment?

Interaction of B cells with membrane antigen results in the formation of the B cell synapse: the B cell receptor (BCR) and antigen concentrate in the contact zone while CD45/B220 and the phosphatase SHP-1 are excluded. This study shows that, unlike in T cells, synapse formation does not require active transport processes (while subsequent antigen extraction and IgM downregulation do). The synapse architecture depends on the available protein ligands in the contact zone. Thus Syk, IgM and Fc receptor accumulation require the presence of ITAM-bearing BCRs, membrane antigen and membrane (IgG-containing) immune complexes, respectively. Remarkably, non-bound proteins are frequently not only homogeneously distributed but excluded from the contact zone. These results suggest that proteins mainly reach the contact zone by undirected diffusion, and in order not to be expelled by molecular crowding they require capture by and fixation to a binding protein.Received 25 August 2004; received after revision 2 November 2004; accepted 17 November 2004     

State of the field: Are the results of science contingent or inevitable?

This paper presents a survey of the literature on the problem of contingency in science. The survey is structured around three challenges faced by current attempts at understanding the conflict between “contingentist” and “inevitabilist” interpretations of scientific knowledge and practice. First, the challenge of definition: it proves hard to define the positions that are at stake in a way that is both conceptually rigorous and does justice to the plethora of views on the issue. Second, the challenge of distinction: some features of the debate suggest that the contingency issue may not be sufficiently distinct from other philosophical debates to constitute a genuine, independent philosophical problem. And third, the challenge of decidability: it remains unclear whether and how the conflict could be settled on the basis of empirical evidence from the actual history of science. The paper argues that in order to make progress in the present debate, we need to distinguish more systematically between different expressions that claims about contingency and inevitability in science can take. To this end, it introduces a taxonomy of different contingency and inevitability claims. The taxonomy has the structure of an ordered quadruple. Each contingency and each inevitability claim contains an answer to the following four questions: (how) are alternatives to current science possible, what types of alternatives are we talking about, how should the alternatives be assessed, and how different are they from actual science?     

Proteasomes in apoptosis: villains or guardians?

The proteasome (multicatalytic proteinase complex, prosome) is a major cytoplasmic proteolytic enzyme, responsible for degradation of the vast majority of intracellular proteins. Proteins degraded by the proteasome are usually tagged with multiple ubiquitin moieties, conjugated to the substrates by a complicated cascade of enzymes. Over the last years, evidence has accumulated that changes in the expression and activity of the different components of the ubiquitin-proteasome system occur during apoptosis. Proteasome inhibitors have been used to induce apoptosis in various cell types, whereas in others, these compounds were able to prevent apoptosis induced by different stimuli. The proteasome mediated step(s) in apoptosis is located upstream of mitochondrial changes and caspase activation, and can involve in different systems Bcl-2, Jun N-terminal kinase, heat shock proteins, Myc, p53, polyamines and other factors.     

The phenocopy concept: Illusion or reality?

Zusammenfassung Verfasser bespricht den Begriff Phänokopie und dessen Grenzen. Er kommt zum Schluss, dieser Begriff sei nützlich, sofern er sich auf experimentell produzierte Phänokopien bezieht, die mit den Erbphänotypen identisch oder ihnen sehr ähnlich sind und deren Entwicklungsgang zum mindesten teilweise mit demjenigen homologer Mutanten übereinstimmt.     

The urokinase receptor: a ligand or a receptor? Story of a sociable molecule

In this last decade, the structure and functions of the receptor for the urokinase-type plasminogen activator have been extensively studied and characterized. This interesting receptor plays a key role in cell adhesion, migration and proliferation. It was identified 20 years ago as the specific cell-surface molecule that could bind and concentrate urokinase on the cell membrane, thus initiating the proteolytic cascade promoted by the activation of plasminogen. The identification of new extracellular ligands, such as vitronectin, and of cell-surface interactors, such as integrins and fMet-Leu-Phe receptors, shed new light on its possible roles, totally independent of the enzymatic properties of its ligand. uPAR ligands and interactors and the functional consequences of the multiple binding capability of this intriguing receptor are reviewed here. Received 19 September 2005; received after revision 4 December 2005; accepted 6 December 2005     

Centrioles: active players or passengers during mitosis?

Centrioles are cylinders made of nine microtubule (MT) triplets present in many eukaryotes. Early studies, where centrosomes were seen at the poles of the mitotic spindle led to their coining as “the organ for cell division”. However, a variety of subsequent observational and functional studies showed that centrosomes might not always be essential for mitosis. Here we review the arguments in this debate. We describe the centriole structure and its distribution in the eukaryotic tree of life and clarify its role in the organization of the centrosome and cilia, with an historical perspective. An important aspect of the debate addressed in this review is how centrioles are inherited and the role of the spindle in this process. In particular, germline inheritance of centrosomes, such as their de novo formation in parthenogenetic species, poses many interesting questions. We finish by discussing the most likely functions of centrioles and laying out new research avenues.     

OV or TOV?

The well-known equation for hydrostatic equilibrium in a static spherically symmetric spacetime supported by an isotropic perfect fluid is referred to as the Oppenheimer–Volkoff (OV) equation or the Tolman–Oppenheimer–Volkoff (TOV) equation in various General Relativity textbooks or research papers. We scrutinize the relevant original publications to argue that the former is the more appropriate terminology.     

Grasping the spirit in nature: Anschauung in Ørsted's epistemology of science and beauty

The intersection between art, poetry, philosophy and science was the leitmotif which guided the lives and careers of romantic natural philosophers including that of the Danish natural philosopher, H. C. Ørsted. A simple model of Ørsted’s career would be one in which it was framed by two periods of philosophical speculation: the youth’s curious and idealistic interest in new attractive thoughts and the experienced man’s mature reflections at the end of his life. We suggest that a closer look at the epistemological aspects of his works on the theory of beauty reveals a connection between this late work and his early philosophical work including experimental philosophy, but also with the work in teaching and textbook writing, that lies in between. The latter includes Ørsted’s view on the application of mathematics in natural philosophy as well as his failed attempt at a genetic presentation of elementary geometry.     

Complementarity and the selection of nature reserves: algorithms and the origins of conservation planning, 1980–1995

This paper reconstructs the history of the introduction and use of iterative algorithms in conservation biology in the 1980s and early 1990s in order to prioritize areas for protection as nature reserves. The importance of these algorithms was that they led to greater economy in spatial extent (“efficiency”) in the selection of areas to represent biological features adequately (that is, to a specified level) compared to older methods of scoring and ranking areas using criteria such as biotic “richness” (the number of features of interest). The development of these algorithms was critical to producing a research program for conservation biology that was distinct from ecology and eventually led to what came to be called systematic conservation planning. Very similar algorithmic approaches were introduced independently in the 1980–1990 period in Australia, South Africa, and (arguably) the United Kingdom. The key rules in these algorithms were the use of rarity and what came to be called complementarity (the number of new or under-represented features in an area relative to those that had already been selected). Because these algorithms were heuristic, they were not guaranteed to produce optimal (most “efficient”) solutions. However, complementarity came to be seen as a principle rather than a rule in an algorithm and its use was also advocated for the former reason. Optimal solutions could be produced by reformulating the reserve selection problem in a mathematical programming formalism and using exact algorithms developed in that context. A dispute over the relevance of full optimality arose and was never resolved. Moreover, exact algorithms could not easily incorporate criteria determining the spatial configuration of networks of selected areas, in contrast to heuristic algorithms. Meanwhile metaheuristic algorithms emerged in the 1990s and came to be seen as a credible more effective alternative to the heuristic algorithms. Ultimately what was important about these developments was that the reserve selection problem came to be viewed a complex optimal decision problem under uncertainty, resource, and other constraints. It was a type of problem that had no antecedent in traditional ecology.     

T cell receptor bias for MHC: co-evolution or co-receptors?

In contrast to antibodies, which recognize antigens in native form, αβ T cell receptors (TCRs) only recognize antigens as peptide fragments bound to MHC molecules, a feature known as MHC restriction. The mechanism by which MHC restriction is imposed on the TCR repertoire is an unsolved problem that has generated considerable debate. Two principal models have been advanced to explain TCR bias for MHC. According to the germline model, MHC restriction is intrinsic to TCR structure because TCR and MHC molecules have co-evolved to conserve germline-encoded TCR sequences with the ability to bind MHC, while eliminating TCR sequences lacking MHC reactivity. According to the selection model, MHC restriction is not intrinsic to TCR structure, but is imposed by the CD4 and CD8 co-receptors that promote signaling by delivering the Src tyrosine kinase Lck to TCR–MHC complexes through co-receptor binding to MHC during positive selection. Here, we review the evidence for and against each model and conclude that both contribute to determining TCR specificity, although their relative contributions remain to be defined. Thus, TCR bias for MHC reflects not only germline-encoded TCR–MHC interactions but also the requirement to form a ternary complex with the CD4 or CD8 co-receptor that is geometrically competent to deliver a maturation signal to double-positive thymocytes during T cell selection.