Homologous recombination in fission yeast: Absence of crossover interference and synaptonemal complex

The study of homologous recombination in the fission yeastSchizosaccharomyces pombe has recently been extended to the cytological analysis of meiotic prophase. Unlike in most eukaryotes no tripartite SC structure is detectable, but linear elements resembling axial cores of other eukaryotes are retained. They may be indispensable for meiotic recombination and proper chromosome segregation in meiosis I. In addition fission yeast shows interesting features of chromosome organization in vegetative and meiotic cells: Centromeres and telomeres cluster and associate with the spindle pole body. The special properties of fission yeast meiosis correlate with the absence of crossover interference in meiotic recombination. These findings are discussed. In addition homologous recombination in fission yeast is reviewed briefly.This article is dedicated to Urs Leupold, the founder of fission yeast genetics.     

Reconsidering the dynamics of reason: Response to Ferrari,Mormann, Nordmann,and Uebel

I address the points raised by the four commentators by indicating how I have been thinking about extending and expanding my perspective since Dynamics of Reason (2001). This involves reinterpreting the Kantian distinction between understanding and sensibility, and thereby rethinking the relativized a priori. I connect these ideas with experimental contexts and technology, as well as with the wider culture context. I suggest implications for the relationships among science, democracy, and religion—and eventually reconceptualizing Kant’s original Enlightenment project.     

Natural history and the formation of the human being: Kant on active forces

In his 1785-review of the Ideen zur Philosophie der Geschichte der Menschheit, Kant objects to Herder's conception of nature as being imbued with active forces. This attack is usually evaluated against the background of Kant's critical project and his epistemological concern to caution against the “metaphysical excess” of attributing immanent properties to matter. In this paper I explore a slightly different reading by investigating Kant's pre-critical account of creation and generation. The aim of this is to show that Kant's struggle with the forces of matter has a long history and revolves around one central problem: that of how to distinguish between the non-purposive forces of nature and the intentional powers of the mind. Given this history, the epistemic stricture that Kant's critical project imposes on him no longer appears to be the primary reason for his attack on Herder. It merely aggravates a problem that Kant has been battling with since his earliest writings.     

From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance

The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.     

A complex of Shc and Ran-GTPase localises to the cell nucleus

The three isoforms of the adaptor protein Shc play diverse roles in cell signalling. For example, the observation of p46 Shc in the nuclei of hepatocellular carcinoma cells suggests a function quite distinct from the better characterised cytoplasmic role. Ligands responsible for the transport of various Shc isoforms into organelles such as the nucleus have yet to be reported. To identify such ligands a far western approach was used to determine the p52 Shc interactome. The Ran-GTPase nuclear transport protein was identified and found to bind to p52 Shc in vitro with low micromolar affinity. Co-immunoprecipitation, pull down and fluorescence lifetime imaging microscopy experiments in stable cells confirmed cellular interaction and nuclear localisation. The nuclear transport factor protein NTF2, which functions in cohort with Ran, was shown to form a complex with both RAN and Shc, suggesting a mechanism for Shc entry into the nucleus as part of a tertiary complex. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 20 October 2008; received after revision 04 December 2008; accepted 15 December 2008     

The experimenters' regress reconsidered: Replication,tacit knowledge,and the dynamics of knowledge generation

This paper revisits the debate between Harry Collins and Allan Franklin, concerning the experimenters' regress. Focusing my attention on a case study from recent psychology (regarding experimental evidence for the existence of a Mozart Effect), I argue that Franklin is right to highlight the role of epistemological strategies in scientific practice, but that his account does not sufficiently appreciate Collins's point about the importance of tacit knowledge in experimental practice. In turn, Collins rightly highlights the epistemic uncertainty (and skepticism) surrounding much experimental research. However, I will argue that his analysis of tacit knowledge fails to elucidate the reasons why scientists often are (and should be) skeptical of other researchers' experimental results. I will present an analysis of tacit knowledge in experimental research that not only answers to this desideratum, but also shows how such skepticism can in fact be a vital enabling factor for the dynamic processes of experimental knowledge generation.     

Induction of cyst formation by low temperature in the dinoflagellateGonyaulax polyedra Stein: Dependence on circadian phase and requirement of light

Encystment, which at a temperature of 15°C is photoperiodically controlled inGonyaulax polyedra, can also be induced by a decrease of temperature, from 20 to 10 or 8°C in the absence of photoperiodic signals. The cyst-inducing capacity of the decrease in temperature depends on the circadian phase: in constant light, the maximum of sensitivity was found at the beginning of subjective night. In a light/dark cycle, however, cyst formation was reduced during dark phase, indicating that light is required for the process of encystment. A similar light dependence was seen in the effect of the physiologically occurring cyst inducer 5-methoxytryptamine, but not in the encystment response to the protonophores monensin and nigericin.     

How not to integrate the history and philosophy of science: a reply to Chalmers

Alan Chalmers uses Robert Boyle’s mechanical philosophy as an example of the irrelevance of ‘philosophy’ to ‘science’ and criticizes my 2006 book Atoms and alchemy for overemphasizing Boyle’s successes. The present paper responds as follows: first, it argues that Chalmers employs an overly simplistic methodology insensitive to the distinction between historical and philosophical claims; second, it shows that the central theses of Atoms and alchemy are untouched by Chalmers’s criticisms; and third, it uses Boyle’s analysis of subordinate causes and his debate with Henry More in the 1670s to demonstrate the inadequacy of Chalmers’s construal of the mechanical philosophy.     

Nuclear science and technology in the Malaysian context: Three phases of technoscientific knowledge transfer (ETTLG)

This essay considers the development of the nuclear science programme in Malaysia from a transnational perspective by examining the interactions between state agents and other external nuclear-knowledge/technology related actors and agents. Going beyond the model of knowledge diffusion that brings together concerns articulated in Harris’s (2011) geographies of long distance knowledge and Reinhardt's (2011) role of the expert in knowledge transfer, the proposed three-phase model of knowledge transfer theorises the pathways undertaken by a late-blooming participant of modern science and technology as the latter moves from epistemic dependency to increasing independence despite the hurdles encountered, and the underdevelopment of many areas of its technoscientific economy. The model considers tensions stemming from the pressures of expediency for meeting national developmental goals on the one side, and the call to support the objectives of basic science on the other. The three phases of the model are epistemic transition, epistemic transplantation and localisation, and epistemic generation (ETTLG). As additional support for the proposed model, three arguments are proffered as deeper explanations of the epistemic goal by using Malaysia as a case study: knowledge transfer for political legitimization, knowledge transfer for countering agnotology, and knowledge transfer for social engineering and science diplomacy.     

Hubris to humility: Tonal volume and the fundamentality of psychophysical quantities

Psychophysics measures the attributes of perceptual experience. The question of whether some of these attributes should be interpreted as more fundamental, or “real,” than others has been answered differently throughout its history. The operationism of Stevens and Boring answers “no,” reacting to the perceived vacuity of earlier debates about fundamentality. The subsequent rise of multidimensional scaling (MDS) implicitly answers “yes” in its insistence that psychophysical data be represented in spaces of low dimensionality. I argue the return of fundamentality follows from a trend toward increasing epistemic humility. Operationism exhibited a kind of hubris in the constitutive role it assigned to the experimenter's presuppositions that is abandoned by the algorithmic methods of MDS. This broad epistemic trend is illustrated by following the trajectory of research on a particular candidate attribute: tonal volume.     

Oxygen consumption and the evolution of order: negentropy criteria applied to the evolution of ants

Optimization of energy use by evolving organisms, predicted by theoretical extensions of the neo-Darwinian theory, i. contrasted with that of irreversible thermodynamics, which predicts an increase in orderliness and thus an increase in energy consumption per unit of biomass. We compared this index with estimates of social complexity among ant genera and species. Our results show that simple optimization models cannot explain experimental data, and that social complexity correlates differently with negentropy at different levels of analysis. Comparing the genera among Formicidae, workers (not colonies) from genera with highly social species are less negentropic than those of socially primitive ones. At the sub-generic level, social complexity correlated positively with negentropy among species, for major workers inAcromyrmex and for minor workers inAtta. The results illustrate the complexity of thermodynamic criteria in the study of evolution but also hint at their usefulness. In this case, they show that two different evolutionary routes to the complex Attini ant societies may exist.     

Thomas Reid and the problem of induction: from common experience to common sense

By the middle of the eighteenth century the new science had challenged the intellectual primacy of common experience in favor of recondite, expert and even counter-intuitive knowledge increasingly mediated by specialized instruments. Meanwhile modern philosophy had also problematized the perceptions of common experience — in the case of David Hume this included our perception of causal relations in nature, a fundamental precondition of scientific endeavor.In this article I argue that, in responding to the ‘problem of induction’ as advanced by Hume, Reid reformulated Aristotelian foundationalism in distinctly modern terms. An educator and mathematician self-consciously working within the framework of the new science, Reid articulated a philosophical foundation for natural knowledge anchored in the human constitution and in processes of adjudication in an emerging modern public sphere of enlightened discourse. Reid thereby transformed one of the bases of Aristotelian science — common experience — into a philosophically and socially justified notion of ‘common sense’. Reid's intellectual concerns had as much to do with the philosophy of science as they did with moral philosophy or epistemology proper, and were bound up with wider social and scientific changes taking place in the early modern period.     

Functionality of the TRPV subfamily of TRP ion channels: add mechano-TRP and osmo-TRP to the lexicon!

Transient receptor potential (TRP) ion channels have been identified as cellular sensors responding to diverse external and internal stimuli. This review will cover the TRPV subfamily that comprises vertebrate and invertebrate members. The six mammalian TRPV channels were demonstrated to function in thermosensation, mechanosensation, osmosensation and Ca²⁺ uptake. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic and chemical stimuli in C. elegans. We will focus here on the role that TRPV ion channels play in mechanosensation and a related sensory (sub-)modality, osmosensation. Received 2 May 2005; received after revision 30 July 2005; accepted 30 August 2005     

Symmetry, asymmetry, and the real possibility of radical change: reply to Kochan

In his critique of my book Heidegger and Marcuse, Jeff Kochan (2006) asserts that I am committed to the possibility of private knowledge, transcendent truths, and individualism. In this reply I argue that he has misinterpreted my analysis of the Challenger disaster and Marcuse’s work. Because I do not dismiss Roger Boisjoly’s doubts about the Challenger launch, Kochan believes that I have abandoned a social concept of knowledge for a reliance on the private knowledge of a single individual. In fact, I consider Boisjoly’s observations just as social, if not as scientific, as the results of rigorous scientific study. Kochan’s reliance on a principle of symmetry derived from science studies to explain such politically charged technological controversies tends to mask the role of power and ideology in social life. Kochan interprets Marcuse as a failed Heideggerian who regresses from Heidegger’s social conception of human being to traditional individualism. I am accused of sharing this view. This interpretation overlooks the importance of the Hegelian–Marxist category of ‘real possibility’ in Marcuse’s work and so mistakes his critique of conformist politics for individualist romanticism. Marcuse always attempted to ground radical opposition in a community of struggle without abandoning the heritage of a long critical tradition. This view I willingly share.     

Copernicus and Fracastoro: the dedicatory letters to Pope Paul III, the history of astronomy, and the quest for patronage

Copernicus’s De revolutionibus (1543) and Girolamo Fracastoro’s Homocentrica (1538) were both addressed to Pope Paul III (1534-1549). Their dedicatory letters represent a rhetorical exercise in advocating an astronomical reform and an attempt to obtain the papal favour. Following on from studies carried out by Westman (1990) and Barker & Goldstein (2003), this paper deals with cultural, intellectual and scientific motives of both texts, and aims at underlining possible relations between them, such as that Copernicus knew of Fracastoro’s Homocentrica, and that at least part of the rhetorical strategy laid out in De revolutionibus’s dedicatory letter can be read as a sophisticated response to Fracastoro’s arguments.     

Surface receptors and functional interactions of human natural killer cells: from bench to the clinic

The past 10years have witnessed dramatic progress in our understanding of how natural killer (NK) cells function and their role in innate immunity. Thanks to an array of inhibitory receptors specific for different HLA class I molecules, human NK cells can sense the decrease or loss of even single alleles at the cell surface. This represents a typical condition of a potential danger, i.e. the presence of tumor or virally infected cells. NK cell triggering and lysis of these cells is mediated by several activating receptors and coreceptors that have recently been identified and cloned. While normal cells are usually resistant to NK-mediated attack, a remarkable exception is represented by dendritic cells (DCs). In their immature form they are susceptible to NK-mediated lysis because of the expression of low levels of surface HLA class I molecules. The process of DC maturation (mDCs) is characterized by the surface expression of high levels of HLA class I molecules. Accordingly, mDCs become resistant to NK cells. A recent major breakthrough highlighted the role played by donor NK cells in allogenic bone marrow transplantation to cure acute myeloid leukemias. Alloreactive NK cells derived from donor hematopoietic precursors not only prevented leukemic relapses, but also prevented graft rejection and graft-versus-host disease.Received 12 March 2003; received after revision 18 April 2003; accepted 30 April 2003     

Histone chaperones: 30 years from isolation to elucidation of the mechanisms of nucleosome assembly and disassembly

Some three decades have passed since the discovery of nucleosomes in 1974 and the first isolation of a histone chaperone in 1978. While various types of histone chaperones have been isolated and functionally analyzed, the elementary processes of nucleosome assembly and disassembly have been less well characterized. Recently, the tertiary structure of a hetero-trimeric complex composed of the histone chaperone CIA/ASF1 and the histone H3-H4 dimer was determined, and this complex was proposed to be an intermediate in nucleosome assembly and disassembly reactions. In addition, CIA alone was biochemically shown to dissociate the histone (H3-H4)₂ tetramer into two histone H3-H4 dimers. This activity suggested that CIA regulates the semi-conservative replication of nucleosomes. Here, we provide an overview of prominent histone chaperones with the goal of elucidating the mechanisms that preserve and modify epigenetic information. We also discuss the reactions involved in nucleosome assembly and disassembly. Received 5 July 2007; received after revision 8 September 2007; accepted 13 September 2007 M. Eitoku, L. Satoa: These authors contributed equally to this work.     

From personality to party: the creation and transmission of Hutchinsonianism, c. 1725-1750

This paper represents a provisional attempt to chart the intellectual construction of Hutchinsonianism over approximately a quarter of a century from the mid-1720s through to the early 1750s. It looks at how Hutchinson’s works were received and fashioned by his first followers, the means they used to communicate their conviction to others, and the extent to which their outlook can be characterised as anti-Newtonian. The paper argues for a slow take up of ‘Hutchinsonian’ views before Spearman and Bate published a collected edition of the master’s works in 1748. This single edition gave Hutchinson’s writings a coherence and a unity they were ill-designed to carry, but it created Hutchinsonianism as an appreciable force in Oxford and elsewhere. The paper concludes that the anti-Newtonian rhetoric of the movement’s founder was increasingly muted in the hands of his followers (with the exception of Bate), and by the 1750s the main bone of contention was less attitudes to Newton than approaches to Hebrew scholarship.