Tumor necrosis factor-mediated cell death: to break or to burst,that’s the question

In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases.     

History of the Lenz–Ising Model 1950–1965: from irrelevance to relevance

This is the second in a series of three papers that charts the history of the Lenz–Ising model (commonly called just the Ising model in the physics literature) in considerable detail, from its invention in the early 1920s to its recognition as an important tool in the study of phase transitions by the late 1960s. By focusing on the development in physicists’ perception of the model’s ability to yield physical insight—in contrast to the more technical perspective in previous historical accounts, for example, Brush (Rev Modern Phys 39: 883–893, 1967) and Hoddeson et al. (Out of the Crystal Maze. Chapters from the History of Solid-State Physics. Oxford University Press, New York, pp. 489–616, 1992)—the series aims to cover and explain in depth why this model went from relative obscurity to a prominent position in modern physics, and to examine the consequences of this change. In the present paper, which is self-contained, I deal with the development from the early 1950s to the 1960s and document that this period witnessed a major change in the perception of the model: In the 1950s it was not in the cards that the model was to become a pivotal tool of theoretical physics in the following decade. In fact, I show, based upon recollections and research papers, that many of the physicists in the 1950s interested in understanding phase transitions saw the model as irrelevant for this endeavor because it oversimplifies the nature of the microscopic constituents of the physical systems exhibiting phase transitions. However, one group, Cyril Domb’s in London, held a more positive view during this decade. To bring out the basis for their view, I analyze in detail their motivation and work. In the last part of the paper I document that the model was seen as much more physically relevant in the early 1960s and examine the development that led to this change in perception. I argue that the main factor behind the change was the realization of the surprising and striking agreement between aspects of the model, notably its critical behavior, and empirical features of the physical phenomena.     

A “SYDE” effect of hierarchical phosphorylation: possible relevance to the cystic fibrosis basic defect

The motif “SYDE”, incorporating the protein kinase CK2 consensus sequence (S-x-x-E) has been found to be phosphorylated at both its serine and tyrosine residues in several proteins. Of special interest is the case of cystic fibrosis Transmembrane-conductance Regulator (CFTR), where this motif is close to the residue (F508), whose deletion is the by far commonest cause of cystic fibrosis. Intriguingly, however, CFTR S511 cannot be phosphorylated by CK2 to any appreciable extent. Using a number of peptide substrates encompassing the CFTR “SYDE” site we have recently shown that: (1) failure of CK2 to phosphorylate the S⁵¹¹YDE motif is due to the presence of Y512; (2) CK2 readily phosphorylates S511 if Y512 is replaced by a phospho-tyrosine; (3) the Src family protein tyrosine kinase Lyn phosphorylates Y512 in a manner that is enhanced by the deletion of F508. These data, in conjunction with the recent observation that by inhibiting CK2 the degradation of F508delCFTR is reduced, lead us to hypothesize that the hierarchical phosphorylation of the motif SYDE by the concerted action of protein tyrosine kinases and CK2 is one of the mechanisms that cooperate to the premature degradation of F508delCFTR.     

Exploring oligodendrocyte guidance: ‘to boldly go where no cell has gone before’

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), originate early in the formation of the brain in specific foci, and migrate throughout the parenchyma. The instructional cues guiding the migration of these progenitor cells must be encoded into their developing environment. Soluble factors as well as membrane-bound cues most likely synergize to create a complex thoroughfare needed to sculpt and organize the brain into a functional organ with white and gray matter. Classically, the focus of many guidance related studies in the CNS has been limited to neuron physiology. However, It is becoming increasingly clear that their lifelong partners, oligodendrocytes, express both ligands and receptors able to both present and respond to these classical cues. In this short review, some recent findings in the Semaphorin and Eph fields will be presented with respect to oligodendrocyte expression and function.Received 4 November 2004; received after revision 1 December 2004; accepted 7 December 2004     

Three unpublished letters to Charles Darwin: the solution to a ‘geometrico-geological’ problem

While Charles Darwin wrote his Observations on South America, he often sought the advice and help of other scientists in solving specific problems. Three letters that the Cambridge geologist and mathematician William Hopkins wrote to Darwin exemplify such aid. In these letters Hopkins was able to show Darwin how he could calculate the position of the sedimentary beds on the Chonos Archipelago, which Darwin had visited. In his first letter Hopkins sent a solution, part of which eluded Darwin. Darwin's letters to Hopkins have not yet been found, but two additional letters gave Darwin the solution he was looking for.     

Back to the tubule: microtubule dynamics in Parkinson’s disease

Cytoskeletal homeostasis is essential for the development, survival and maintenance of an efficient nervous system. Microtubules are highly dynamic polymers important for neuronal growth, morphology, migration and polarity. In cooperation with several classes of binding proteins, microtubules regulate long-distance intracellular cargo trafficking along axons and dendrites. The importance of a delicate interplay between cytoskeletal components is reflected in several human neurodegenerative disorders linked to abnormal microtubule dynamics, including Parkinson’s disease (PD). Mounting evidence now suggests PD pathogenesis might be underlined by early cytoskeletal dysfunction. Advances in genetics have identified PD-associated mutations and variants in genes encoding various proteins affecting microtubule function including the microtubule-associated protein tau. In this review, we highlight the role of microtubules, their major posttranslational modifications and microtubule associated proteins in neuronal function. We then present key evidence on the contribution of microtubule dysfunction to PD. Finally, we discuss how regulation of microtubule dynamics with microtubule-targeting agents and deacetylase inhibitors represents a promising strategy for innovative therapeutic development.     

Reverse transendothelial cell migration in inflammation: to help or to hinder?

The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support “reverse” transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation.     

Liver cell therapy: is this the end of the beginning?

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.     

Cerivastatin: a cellular and molecular drug for the future?

The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market - the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future. Received 29 May 2002; received after revision 23 August 2002; accepted 26 August 2002 RID="*" ID="*"Corresponding author.     

Epithelial cell senescence: an adaptive response to pre-carcinogenic stresses?

Senescence is a cell state occurring in vitro and in vivo after successive replication cycles and/or upon exposition to various stressors. It is characterized by a strong cell cycle arrest associated with several molecular, metabolic and morphologic changes. The accumulation of senescent cells in tissues and organs with time plays a role in organismal aging and in several age-associated disorders and pathologies. Moreover, several therapeutic interventions are able to prematurely induce senescence. It is, therefore, tremendously important to characterize in-depth, the mechanisms by which senescence is induced, as well as the precise properties of senescent cells. For historical reasons, senescence is often studied with fibroblast models. Other cell types, however, much more relevant regarding the structure and function of vital organs and/or regarding pathologies, are regrettably often neglected. In this article, we will clarify what is known on senescence of epithelial cells and highlight what distinguishes it from, and what makes it like, replicative senescence of fibroblasts taken as a standard.     

A researcher’s guide to the galaxy of IRESs

The idea of internal initiation is frequently exploited to explain the peculiar translation properties or unusual features of some eukaryotic mRNAs. In this review, we summarize the methods and arguments most commonly used to address cases of translation governed by internal ribosome entry sites (IRESs). Frequent mistakes are revealed. We explain why “cap-independent” does not readily mean “IRES-dependent” and why the presence of a long and highly structured 5′ untranslated region (5′UTR) or translation under stress conditions cannot be regarded as an argument for appealing to internal initiation. We carefully describe the known pitfalls and limitations of the bicistronic assay and artefacts of some commercially available in vitro translation systems. We explain why plasmid DNA transfection should not be used in IRES studies and which control experiments are unavoidable if someone decides to use it anyway. Finally, we propose a workflow for the validation of IRES activity, including fast and simple experiments based on a single genetic construct with a sequence of interest.     

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     

Colligation in modelling practices: From Whewell’s tides to the San Francisco Bay Model

“Colligation”, a term first introduced in philosophy of science by William Whewell (1840), today sparks a renewed interest beyond Whewell scholarship. In this paper, we argue that adopting the notion of colligation in current debates in philosophy of science can contribute to our understanding of scientific models. Specifically, studying colligation allows us to have a better grasp of how integrating diverse model components (empirical data, theory, useful idealization, visual and other representational resources) in a creative way may produce novel generalizations about the phenomenon investigated. Our argument is built both on the theoretical appraisal of Whewell’s philosophy of science and the historical rehabilitation of his scientific work on tides. Adopting a philosophy of science in practice perspective, we show how colligation emerged from Whewell’s empirical work on tides. The production of idealized maps (“cotidal maps”) illustrates the unifying and creative power of the activity of colligating in scientific practice. We show the importance of colligation in modelling practices more generally by looking at its epistemic role in the construction of the San Francisco Bay Model.     

From ‘Beastly Philosophy’ to Medical Genetics: Eugenics in Russia and the Soviet Union

This essay offers an overview of the three distinct periods in the development of Russian eugenics: Imperial (1900–1917), Bolshevik (1917–1929), and Stalinist (1930–1939). Began during the Imperial era as a particular discourse on the issues of human heredity, diversity, and evolution, in the early years of the Bolshevik rule eugenics was quickly institutionalized as a scientific discipline—complete with societies, research establishments, and periodicals—that aspired an extensive grassroots following, generated lively public debates, and exerted considerable influence on a range of medical, public health, and social policies. In the late 1920s, in the wake of Joseph Stalin's ‘Great Break’, eugenics came under intense critique as a ‘bourgeois’ science and its proponents quickly reconstituted their enterprise as ‘medical genetics’. Yet, after a brief period of rapid growth during the early 1930s, medical genetics was dismantled as a ‘fascist science’ towards the end of the decade. Based on published and original research, this essay examines the factors that account for such an unusual—as compared to the development of eugenics in other locales during the same period—historical trajectory of Russian eugenics.     

Introduction to the special issue Hermann Weyl and the philosophy of the ‘New Physics’

This Special Issue Hermann Weyl and the Philosophy of the ‘New Physics’ has two main objectives: first, to shed fresh light on the relevance of Weyl's work for modern physics and, second, to evaluate the importance of Weyl's work and ideas for contemporary philosophy of physics. Regarding the first objective, this Special Issue emphasizes aspects of Weyl's work (e.g. his work on spinors in n dimensions) whose importance has recently been emerging in research fields across both mathematical and experimental physics, as well as in the history and philosophy of physics. Regarding the second objective, this Special Issue addresses the relevance of Weyl's ideas regarding important open problems in the philosophy of physics, such as the problem of characterizing scientific objectivity and the problem of providing a satisfactory interpretation of fundamental symmetries in gauge theories and quantum mechanics. In this Introduction, we sketch the state of the art in Weyl studies and we summarize the content of the contributions to the present volume.     

To be disordered or not to be disordered: is that still a question for proteins in the cell?

There is ample evidence that many proteins or regions of proteins lack a well-defined folded structure under native-like conditions. These are called intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). Whether this intrinsic disorder is also their main structural characteristic in living cells has been a matter of intense debate. The structural analysis of IDPs became an important challenge also because of their involvement in a plethora of human diseases, which made IDPs attractive targets for therapeutic development. Therefore, biophysical approaches are increasingly being employed to probe the structural and dynamical state of proteins, not only in isolation in a test tube, but also in a complex biological environment and even within intact cells. Here, we survey direct and indirect evidence that structural disorder is in fact the physiological state of many proteins in the proteome. The paradigmatic case of α-synuclein is used to illustrate the controversial nature of this topic.     

Aging clock: the watchmaker’s masterpiece

The phenomenon of cellular senescence has been known for almost four decades. Yet, until very recently, the molecular mechanisms that lead to senescence have been poorly understood. However, substantial progress has been made in the last few years toward identifying the pathways executing senescence. This r view focuses on two major advances in this field, the telomere aging clock theory and the cell cycle regulatory mechanisms in senescent cells. These recent studies indicate that cellular senescence is a highly elaborate and active process, which presumably works as an anti-oncogenic mechanism.     

Two cell types in monoamine-containing ‘liquor contacting’ neuron system on the frog brain

Summary By means of an immunofluorescent technique, liquor contacting neurons, serotonergic in nature were demonstrated in the paraventricular organ and in the nucleus infundibularis dorsalis, and neurons catecholaminergic in nature were noted in the preoptic recess organ and in the caudal part of the 4th ventricle.