A structural view of translation initiation in bacteria

The assembly of the protein synthesis machinery occurs during translation initiation. In bacteria, this process involves the binding of messenger RNA(mRNA) start site and fMet-tRNA^fMet to the ribosome, which results in the formation of the first codon-anticodon interaction and sets the reading frame for the decoding of the mRNA. This interaction takes place in the peptidyl site of the 30S ribosomal subunit and is controlled by the initiation factors IF1, IF2 and IF3 to form the 30S initiation complex. The binding of the 50S subunit and the ejection of the IFs mark the irreversible transition to the elongation phase. Visualization of these ligands on the ribosome has been achieved by cryo-electron microscopy and X-ray crystallography studies, which has helped to understand the mechanism of translation initiation at the molecular level. Conformational changes associated with different functional states provide a dynamic view of the initiation process and of its regulation. Received 16 July 2008; received after revision 31 August 2008; accepted 10 September 2008 A. Simonetti, S. Marzid: These authors contributed equally to this work.     

Understanding microtubule dynamics for improved cancer therapy

Microtubules (MTs), key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments. MT dynamics are highly regulated both spacially and temporally by several MT-related proteins, themselves regulated by several kinases and phosphatases via signaling cascades, and also by coordinated interactions with actin cytoskeleton and adhesion sites. Regulation of MT dynamics is crucial for mitosis, cell migration, cell signaling and trafficking. MT-targeted drugs (MTDs), which constitute a major anticancer drug family with antimitotic and antiangiogenic properties, inhibit tumor progression mainly by altering MT dynamics in both cancer and endothelial cells. Identification of proteins regulating the MT network will lead to a better understanding of tumor progression regulators and will be helpful in improving cancer therapy. Received 22 July 2005; received after revision 8 September 2005; accepted 12 September 2005     

Autoinhibition of TBCB regulates EB1-mediated microtubule dynamics

Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP-Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO^? present in TBCB, which is similar to the EEY/F-COO^? element characteristic of EB proteins, CLIP-170, and α-tubulin, is required for TBCE–TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing α-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation.     

A structural view of nuclear hormone receptor: endocrine disruptor interactions

Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system by interfering with hormone biosynthesis, metabolism, or action. The molecular mechanisms of EDCs involve different pathways including interactions with nuclear hormone receptors (NHRs) which are primary targets of a large variety of environmental contaminants. Here, based on the crystal structures currently available in the Protein Data Bank, we review recent studies showing the many ways in which EDCs interact with NHRs and impact their signaling pathways. Like the estrogenic chemical diethylstilbestrol, some EDCs mimic the natural hormones through conserved protein–ligand contacts, while others, such as organotins, employ radically different binding mechanisms. Such structure-based knowledge, in addition to providing a better understanding of EDC activities, can be used to predict the endocrine-disrupting potential of environmental pollutants and may have applications in drug discovery.     

Regulation of end-binding protein EB1 in the control of microtubule dynamics

The regulation of microtubule dynamics is critical to ensure essential cell functions, such as proper segregation of chromosomes during mitosis or cell polarity and migration. End-binding protein 1 (EB1) is a plus-end-tracking protein (+TIP) that accumulates at growing microtubule ends and plays a pivotal role in the regulation of microtubule dynamics. EB1 autonomously binds an extended tubulin-GTP/GDP-Pi structure at growing microtubule ends and acts as a molecular scaffold that recruits a large number of regulatory +TIPs through interaction with CAP-Gly or SxIP motifs. While extensive studies have focused on the structure of EB1-interacting site at microtubule ends and its role as a molecular platform, the mechanisms involved in the negative regulation of EB1 have only started to emerge and remain poorly understood. In this review, we summarize recent studies showing that EB1 association with MT ends is regulated by post-translational modifications and affected by microtubule-targeting agents. We also present recent findings that structural MAPs, that have no tip-tracking activity, physically interact with EB1 to prevent its accumulation at microtubule plus ends. These observations point out a novel concept of “endogenous EB1 antagonists” and emphasize the importance of finely regulating EB1 function at growing microtubule ends.     

A molecular view of cardiogenesis

Cardiac development involves a complex integration of subcellular processes into multicellular and, finally, whole organ effects. Until recently it has been difficult to investigate the genetic control of this organ level differentiation of the heart. The proliferation of molecular biology methodologies has provided mechanisms to directly investigate the control of these processes. This article focuses on molecular lines of research on two key areas in cardiac development: the regulation of expression of sarcomeric contractile and regulatory proteins, and atrial natriuretic factor. Molecular approaches are described which have allowed investigators to begin to determine the tissue and stage-specific expression of genes, to locate those genes in the genome, determine their sequences, and to directly investigate the mechanisms controlling their expression.     

A view on intramembraneous particles

Summary Intramembraneous particles of the outer membrane ofEscherichia coli show complementary pits on the opposite fracture face. This complementarity characteristic has been discussed in relation to the nature of the particle and the mode of fracturing.Acknowledgment. We thank Dr Lugtenberg for his active support and critical comments and Mrs J. Leunissen-Bijvelt for her technical assistance.     

Styles of reasoning: A pluralist view

Styles of reasoning are important devices to understand scientific practice. As I use the concept, a style of reasoning is a pattern of inferential relations that are used to select, interpret, and support evidence for scientific results. In this paper, I defend the view that there is a plurality of styles of reasoning: different domains of science often invoke different styles. I argue that this plurality is an important source of disunity in scientific practice, and it provides additional arguments in support of the disunity claim. I also contrast Ian Hacking’s broad characterization of styles of reasoning with a narrow understanding that I favor. Drawing on examples from molecular biology, chemistry and mathematics, I argue that differences in style of reasoning lead to differences in the way the relevant results are obtained and interpreted. The result is a pluralist view about styles of reasoning that is sensitive to nuances of inferential relations in scientific activity.     

A unified view of statistical forecasting procedures

A large number of statistical forecasting procedures for univariate time series have been proposed in the literature. These range from simple methods, such as the exponentially weighted moving average, to more complex procedures such as Box–Jenkins ARIMA modelling and Harrison–Stevens Bayesian forecasting. This paper sets out to show the relationship between these various procedures by adopting a framework in which a time series model is viewed in terms of trend, seasonal and irregular components. The framework is then extended to cover models with explanatory variables. From the technical point of view the Kalman filter plays an important role in allowing an integrated treatment of these topics.     

A non representationalist view of model explanation

In this paper, I examine two idealized models in astrophysics, with the aim of showing that the idealizations in these models play an important explanatory role. I argue, against many representationalists, that it is because of the idealizations in these models, rather than in spite of them, that the models turn out to have explanatory power. In many cases, this claim can be extended to the use of idealized models in the sciences more generally, and thus it gives important insight into the nature of model explanation.     

Action and interactions at microtubule ends

Microtubule dynamic instability is fundamentally important to the way cells respond to their environment and segregate their genetic material. A disparate class of proteins defined by their localisation to growing microtubule plus ends ('+TIPS') play a key role in controlling microtubule dynamics and organisation. They directly impact upon the behaviour of the microtubule tip and link this structure to interfaces that include kinetochores and the cortex of the cell. Surprisingly, some +TIPs also have important functions at the microtubule minus end. These properties contribute to the important roles played by +TIPs in processes such as mitosis and cell migration. This review examines how recent advances have impacted our understanding of +TIP function in mammalian cells, with emphasis on the emergence of the EB1 family as a core component of +TIP activities. An overview of the use of +TIP imaging as a tool for the cell biologist is also presented.     

A dynamic view of peptides and proteins in membranes

Biological membranes are highly dynamic supramolecular arrangements of lipids and proteins, which fulfill key cellular functions. Relatively few high-resolution membrane protein structures are known to date, although during recent years the structural databases have expanded at an accelerated pace. In some instances the structures of reaction intermediates provide a stroboscopic view on the conformational changes involved in protein function. Other biophysical approaches add dynamic aspects and allow one to investigate the interactions with the lipid bilayers. Membrane-active peptides fulfill many important functions in nature as they act as antimicrobials, channels, transporters or hormones, and their studies have much increased our understanding of polypeptide-membrane interactions. Interestingly several proteins have been identified that interact with the membrane as loose arrays of domains. Such conformations easily escape classical high-resolution structural analysis and the lessons learned from peptides may therefore be instructive for our understanding of the functioning of such membrane proteins. Received 11 March 2008; received after revision 2 May 2008; accepted 5 May 2008     

A branching space-times view on quantum error correction

In this paper we describe some first steps for bringing the framework of branching space-times (BST) to bear on quantum information theory. Our main application is quantum error correction. It is shown that BST offers a new perspective on quantum error correction: as a supplement to the orthodox slogan, “fight entanglement with entanglement”, we offer the new slogan, “fight indeterminism with indeterminism”.     

Statistical mechanics and thermodynamics: A Maxwellian view

One finds, in Maxwell's writings on thermodynamics and statistical physics, a conception of the nature of these subjects that differs in interesting ways from the way they are usually conceived. In particular, though—in agreement with the currently accepted view—Maxwell maintains that the second law of thermodynamics, as originally conceived, cannot be strictly true, the replacement he proposes is different from the version accepted by most physicists today. The modification of the second law accepted by most physicists is a probabilistic one: although statistical fluctuations will result in occasional spontaneous differences in temperature or pressure, there is no way to predictably and reliably harness these to produce large violations of the original version of the second law. Maxwell advocates a version of the second law that is strictly weaker; the validity of even this probabilistic version is of limited scope, limited to situations in which we are dealing with large numbers of molecules en masse and have no ability to manipulate individual molecules. Connected with this is his conception of the thermodynamic concepts of heat, work, and entropy; on the Maxwellian view, these are concept that must be relativized to the means we have available for gathering information about and manipulating physical systems. The Maxwellian view is one that deserves serious consideration in discussions of the foundation of statistical mechanics. It has relevance for the project of recovering thermodynamics from statistical mechanics because, in such a project, it matters which version of the second law we are trying to recover.     

A view of progress in the chemistry of indole alkaloids

Zusammenfassung Neuere Erkenntnisse der theoretischen Chemie, Entwicklungen der chemischen Experimentierkunst und neue und verbesserte physikalische Instrumentation haben die Entwicklung der Indolalkaloidchemie im letzten Dezennium entscheidend gefördert. Die erfolgreiche Konstitutionsermittlung einer Reihe längst bekannter Indolalkaloide wurde dadurch ermöglicht. Ihre Konstitution sowie die Strukturen unlängst isolierter Indolbasen lassen auf eine grosse Mannigfaltigkeit im strukturellen Bau der Indolalkaloide schliessen. Die Biosynthese der Indolalkaloide wird kurz diskutiert, zusammen mit Kommentaren über den Ursprung des Rings E und der Carboxylgruppe in den Yohimbinen.

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This essay reflects the authors' approach to this subject. Only the major theme is developed but certain ideas buried in text may act as catalysts for further thought.