BonJour on explanation and skepticism

Laurence BonJour, among others, has argued that inference to the best explanation allows us to reject skeptical hypotheses in favor of our common-sense view of the world. BonJour considers several skeptical hypotheses, specifically: (i) our experiences arise by mere chance, uncaused; (ii) the simple hypothesis which states merely that our experiences are caused unveridically; and (iii) an elaborated hypothesis which explains in detail how our unveridical experiences are brought about. A central issue is whether the coherence of one’s experience makes that experience more likely to be veridical. BonJour’s recent treatment of “analog” and “digital” skeptical hypotheses is also discussed. I argue that, although there are important lessons to be learned from BonJour’s writings, his use of inference to the best explanation against skepticism is unsuccessful.     

Control of cell growth: Rag GTPases in activation of TORC1

The target of rapamycin (TOR) is a central regulator controlling cell growth. TOR is highly conserved from yeast to mammals, and is deregulated in human cancers and diabetes. TOR complex 1 (TORC1) integrates signals from growth factors, cellular energy status, stress, and amino acids to control cell growth, mitochondrial metabolism, and lipid biosynthesis. The mechanisms of growth factors and cellular energy status in regulating TORC1 have been well established, whereas the mechanism by which amino acid induces TORC1 remains largely unknown. Recent studies revealed that Rag GTPases play a central role in the regulation of TORC1 activation in response to amino acids. In this review, we will discuss the recent progress in our understanding of Rag GTPase-regulated TORC1 activation in response to amino acids. Particular focus will be given to the function of Rag GTPases in TORC1 activation and how Rag GTPases are regulated by amino acids.     

Reference, ontological replacement and Neo-Kantianism: a reply to Sankey

Contrary to Sankey’s central assumption, incommensurability does not imply incomparability of content, nor threaten scientific realism by challenging the rationality of theory comparison. Moreover, Sankey equivocates between reference to specific entities by statements used to test theories and reference to kinds by theories themselves. This distinction helps identify and characterize the genuine threat that incommensurability poses to realism, which is ontological discontinuity as evidenced in the historical record: Successive theories reclassify objects into mutually exclusive sets of kinds to which they refer. That is why claiming that scientific progress is an increasingly better approximation to truth is difficult to justify. Similarly, Sankey’s attack on neo-Kantian antirealist positions is based on his misunderstanding of some of the central terms of those positions, making most of his attack on them ineffectual, including his diagnosis of their incoherence. We conclude by reiterating our conviction that in this debate meta-incommensurability plays an important role.     

Partial complementation of a DNA ligase I deficiency by DNA ligase III and its impact on cell survival and telomere stability in mammalian cells

DNA ligase I (LigI) plays a central role in the joining of strand interruptions during replication and repair. In our current study, we provide evidence that DNA ligase III (LigIII) and XRCC1, which form a complex that functions in single-strand break repair, are required for the proliferation of mammalian LigI-depleted cells. We show from our data that in cells with either dysfunctional LigI activity or depleted of this enzyme, both LigIII and XRCC1 are retained on the chromatin and accumulate at replication foci. We also demonstrate that the LigI and LigIII proteins cooperate to inhibit sister chromatid exchanges but that only LigI prevents telomere sister fusions. Taken together, these results suggest that in cells with dysfunctional LigI, LigIII contributes to the ligation of replication intermediates but not to the prevention of telomeric instability.     

Galanin – 25 years with a multitalented neuropeptide

Galanin has diverse physiological functions, including nociception, arousal/sleep regulation, cognition, and many aspects of neuroendocrine activities that are associated with feeding, energy metabolism, thermoregulation, osmotic and water balance, and reproduction. This review will provide a brief overview of galanin actions in some major neuroendocrine processes. Most of the recent data are about the role of galanin in the central regulation of food intake and energy metabolism, and to some extent, in the regulation of reproduction. It seems that galanin plays a modulatory rather than regulatory role in the central and peripheral branches of the neuroendocrine systems. In the hypothalamus, it functions as a neurotransmitter/neuromodulator. In the pituitary and the peripheral endocrine glands, it acts via its receptors (GALRs) in a paracrine/autocrine fashion. The development of new, selective and potent antagonists of GALRs should keep advancing our knowledge not only in the physiology but also the pathophysiology of galanin as well.     

gamma-Aminobutyric acid and cardiovascular function

Evidence supporting the hypothesis that GABA-ergic mechanisms are involved in controlling mammalian cardiovascular function has been reviewed and analyzed. In vivo and in vitro studies with GABA-agonists and GABA-antagonists have revealed that activation of GABA-receptors is involved in the control of blood pressure and heart rate. Further studies conducted with agents that modify central and/or peripheral GABA-ergic systems could lead to the discovery of drugs that might be useful for treating certain cardiovascular disorders in man, such as hypertension and stroke, and should increase our understanding of the pathophysiological bases of such disorders.     

Molecular biology of water and salt regulation in the kidney

The kidney plays a central role in the regulation of the salt and water balance, which depends upon an array of solute and water transporters in the renal tubules and upon vascular elements in the various regions of the kidney. Many recent studies have improved our understanding of this process. In this review, we summarize the current data on the molecules involved in sodium and water transport in the renal tubules, focusing in particular on aquaporins and renal sodium transporters and channels.     

The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus

Ribavirin, a broad spectrum antiviral agent, in conjunction with interferon forms the current standard of treatment for hepatitis C virus (HCV) infection in humans. While ribavirin alone fails to induce a significant antiviral response, in combination with interferon, ribavirin dramatically improves the long-term outcome of therapy. The predominant mechanism(s) of ribavirin action against HCV, are yet to be established. In this review, we examine the current status of our understanding of the metabolism, pharmacokinetics and mechanisms of the antiviral activity of ribavirin against HCV, all of which are central to the rational identification of improved treatment protocols. Received 30 September 2005; received after revision 20 November 2005; accepted 7 December 2005     

Comparing peripheral glial cell differentiation in <Emphasis Type="Italic">Drosophila</Emphasis> and vertebrates

In all complex organisms, the peripheral nerves ensure the portage of information from the periphery to central computing and back again. Axons are in part amazingly long and are accompanied by several different glial cell types. These peripheral glial cells ensure electrical conductance, most likely nuture the long axon, and establish and maintain a barrier towards extracellular body fluids. Recent work has revealed a surprisingly similar organization of peripheral nerves of vertebrates and Drosophila. Thus, the genetic dissection of glial differentiation in Drosophila may also advance our understanding of basic principles underlying the development of peripheral nerves in vertebrates.     

Computational protein function prediction: Are we making progress?

The computational prediction of gene and protein function is rapidly gaining ground as a central undertaking in computational biology. Making sense of the flood of genomic data requires fast and reliable annotation. Many ingenious algorithms have been devised to infer a protein's function from its amino acid sequence, 3D structure and chromosomal location of the encoding genes. However, there are significant challenges in assessing how well these programs perform. In this article we explore those challenges and review our own attempt at assessing the performance of those programs. We conclude that the task is far from complete and that a critical assessment of the performance of function prediction programs is necessary to make true progress in computational function prediction.     

Dual role of cAMP duringDictyostelium development

cAMP plays an essential role duringDictyostelium development both outside and inside the cell. Membrane-bound receptors and adenylyl cyclase are responsible for sensing and producing extracellular cAMP, whereas a phosphodiesterase is responsible for maintaining a low basal level. The molecular events underlying this type of hormone like signalling, which are now beginning to be deciphered, will be presented, in the light of cAMP analogue studies. The importance of intracellular cAMP for cell differentiation has been demonstrated by the central role of the cAMP dependent protein kinase. Mutants as well as strains obtained by reverse genetics will be reviewed which lead to our current understanding of the role of intracellular cAMP in the differentiation of both stalk and spore cells.     

A choice-semantical approach to theoretical truth

A central topic in the logic of science concerns the proper semantic analysis of theoretical sentences, that is sentences containing theoretical terms. In this paper, we present a novel choice-semantical account of theoretical truth based on the epsilon-term definition of theoretical terms. Specifically, we develop two ways of specifying the truth conditions of theoretical statements in a choice functional semantics, each giving rise to a corresponding logic of such statements. In order to investigate the inferential strength of these logical systems, we provide a translation of each truth definition into a modal definition of theoretical truth. Based on this, we show that the stronger notion of choice-semantical truth captures more adequately our informal semantic understanding of scientific statements.     

Sleeping sickness and the brain

Recent progress in understanding the neuro-pathological mechanisms of sleeping sickness reveals a complex relationship between the trypanosome parasite that causes this disease and the host nervous system. The pathology of late-stage sleeping sickness, in which the central nervous system is involved, is complicated and is associated with disturbances in the circadian rhythm of sleep. The blood-brain barrier, which separates circulating blood from the central nervous system, regulates the flow of materials to and from the brain. During the course of disease, the integrity of the blood-brain barrier is compromised. Dysfunction of the nervous system may be exacerbated by factors of trypanosomal origin or by host responses to parasites. Microscopic examination of cerebrospinal fluid remains the best way to confirm late-stage sleeping sickness, but this necessitates a risky lumbar puncture. Most drugs, including many trypanocides, do not cross the blood-brain barrier efficiently. Improved diagnostic and therapeutic approaches are thus urgently required. The latter might benefit from approaches which manipulate the blood-brain barrier to enhance permeability or to limit drug efflux. This review summarizes our current understanding of the neurological aspects of sleeping sickness, and envisages new research into blood-brain barrier models that are necessary to understand the interactions between trypanosomes and drugs active against them within the host nervous system. Received 10 October 2001; received after revision 29 November 2001; accepted 5 December 2001     

Craft,money and mercy: an apothecary's self-portrait in sixteenth-century Bologna1

The apothecary occupied a liminal position in early modern society between profit and healing. Finding ways to distance their public image from trade was a common problem for apothecaries across Europe. This article uses the case of a Bolognese apothecary, Filippo Pastarino, to address the question of how early modern apothecaries chose to represent themselves to political authorities and to the wider public. ‘Mercy’, alongside ‘craft’, was a pillar of apothecaries’ social identity. By contrast, no matter how central financial transactions (‘money’) were to their activity, apothecaries did not want to be perceived as merchants. Thus, the assistance and advice apothecaries provided to patients and customers resulted as central aspects of their social role. In this context, Bolognese apothecaries aimed to defend their current status, which had been challenged by naturalist Ulysses Aldrovandi, city authorities and local monasteries. However, Pastarino's claims can also be seen as antecedents to the self-legitimizing strategy that seventeenth-century artisans deployed when faced with the need to enhance their new status as natural philosophers. The present study attributes a name, a date of birth and a shop to Filippo Pastarino, revising previous interpretations. More broadly, by focusing on how these artisans defended their position in the city it enriches our understanding of the self-representation of apothecaries.     

Mechanisms of endothelial cell migration

Cell migration plays a central role in a variety of physiological and pathological processes during our whole life. Cellular movement is a complex, tightly regulated multistep process. Although the principle mechanisms of migration follow a defined general motility cycle, the cell type and the context of moving influences the detailed mode of migration. Endothelial cells migrate during vasculogenesis and angiogenesis but also in a damaged vessel to restore vessel integrity. Depending on the situation they migrate individually, in chains or sheets and complex signaling, intercellular signals as well as environmental cues modulate the process. Here, the different modes of cell migration, the peculiarities of endothelial cell migration and specific guidance molecules controlling this process will be reviewed.     

The transcendental method from Newton to Kant

Kant’s transcendental method, as applied to natural philosophy, considers the laws of physics as conditions of the possibility of experience. A more modest transcendental project is to show how the laws of motion explicate the concepts of motion, force, and causal interaction, as conditions of the possibility of an objective account of nature. This paper argues that such a project is central to the natural philosophy of Newton, and explains some central aspects of the development of his thinking as he wrote the Principia. One guiding scientific aim was the dynamical analysis of any system of interacting bodies, and in particular our solar system; the transcendental question was, what are the conceptual prerequisites for such an analysis? More specifically, what are the conditions for determining “true motions” within such a system—for posing the question of “the frame of the system of the world” as an empirical question? A study of the development of Newton’s approach to these questions reveals surprising connections with his developing conceptions of force, causality, and the relativity of motion. It also illuminates the comparison between his use of the transcendental method and that of Euler and Kant.     

Model instability in predictive exchange rate regressions

In this paper we aim to improve existing empirical exchange rate models by accounting for uncertainty with respect to the underlying structural representation. Within a flexible Bayesian framework, our modeling approach assumes that different regimes are characterized by commonly used structural exchange rate models, with transitions across regimes being driven by a Markov process. We assume a time-varying transition probability matrix with transition probabilities depending on a measure of the monetary policy stance of the central bank at home and in the USA. We apply this model to a set of eight exchange rates against the US dollar. In a forecasting exercise, we show that model evidence varies over time, and a model approach that takes this empirical evidence seriously yields more accurate density forecasts for most currency pairs considered.     

Does geographic location matter to stock return predictability?

Building on recent and growing evidence that geographic location influences information diffusion, this paper examines the relation between firm's location and the predictability of stock returns. We hypothesize that returns on a portfolio composed of firms located in central areas are more likely to follow a random walk than returns on a portfolio composed of firms located in remote areas. Using a battery of variance ratio tests, we find strong and robust support for our prediction. In particular, we show that the returns on a portfolio composed of the 500 largest urban firms follow a random walk; however, all variance ratio tests reject the random walk hypothesis for a portfolio that includes the 500 largest rural firms. Our results are robust to alternative definitions of firm's location and portfolio formation.