The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis?

Ohno’s hypothesis states that dosage compensation in mammals evolved in two steps: a twofold hyperactivation of the X chromosome in both sexes to compensate for gene losses on the Y chromosome, and silencing of one X (X-chromosome inactivation, XCI) in females to restore optimal dosage. Recent tests of this hypothesis have returned contradictory results. In this review, we explain this ongoing controversy and argue that a novel view on dosage compensation evolution in mammals is starting to emerge. Ohno’s hypothesis may be true for a few, dosage-sensitive genes only. If so few genes are compensated, then why has XCI evolved as a chromosome-wide mechanism? This and several other questions raised by the new data in mammals are discussed, and future research directions are proposed.     

Darier’s disease: a calcium-signaling perspective

Ca²⁺ influx evoked across the plasma membrane upon internal store depletion is essential for a myriad of cellular functions including gene expression, cell proliferation, differentiation and even apoptosis. Darier’s disease (DD), an autosomal dominant inherited disorder of the skin, arising due to mutations in the isoform 2 of the sarco (endo) plasmic reticulum Ca²⁺ ATPase (SERCA2), exemplifies an anomaly of Ca²⁺ signaling disturbances. Owing to loss of function mutations in SERCA2, keratinocytes in DD patients have a reduced pool of endoplasmic reticulum (ER) Ca²⁺. Importantly, the status of ER Ca²⁺ is critical for the activation of a class of plasma membrane Ca²⁺ channels referred to as store operated Ca²⁺ channels (SOCs). The widely expressed transient receptor potential (TRP) family of channels is proposed to be SOCs. In this review we discuss DD from the viewpoint of Ca²⁺ signaling and present a potential role for TRPC1 in the disease pathogenesis. Received 30 August 2007; received after revision 17 October 2007; accepted 6 November 2007     

Whittaker’s analytical dynamics: a biography

Originally published in 1904, Whittaker’s A Treatise on the Analytical Dynamics of Particles and Rigid Bodies soon became a classic of the subject and has remained in print for most of these 108 years. In this paper, we follow the book as it develops from a report that Whittaker wrote for the British Society for the Advancement of Science to its influence on Dirac’s version of quantum mechanics in the 1920s and beyond.     

Bisecting the trapezoid: tracing the origins of a Babylonian computation of Jupiter’s motion

Archive for History of Exact Sciences - Between ca. 400 and 50 BCE, Babylonian astronomers used mathematical methods for predicting ecliptical positions, times and other phenomena of the moon and...     

Newton’s De gravitatione: a review and reassessment

The widely accepted supposition that Newton’s De gravitatione was written in 1684/5 just before composing the Principia is examined. The basis for this determination has serious difficulties starting with the failure to examine the numerical estimates for the resistance of aether. The estimated range is not nearly nil as claimed but comparable with air at or near the earth’s surface. Moreover, the evidence provided most likely stems from experiments by Boyle, Hooke, and others in the 1660s and does not use evidence available in the late 1684. The document supports Newton’s contention that the aether medium incorporates very large voids thereby proving that body and space differ but does by no means completely reject its corporeal nature or eliminate its resistance. Newton’s use of the term inertia provides no conclusive evidence for a late date as often claimed and his definition of gravitas is difficult to reconcile with a late one.     

Superposition: on Cavalieri’s practice of mathematics

Bonaventura Cavalieri has been the subject of numerous scholarly publications. Recent students of Cavalieri have placed his geometry of indivisibles in the context of early modern mathematics, emphasizing the role of new geometrical objects, such as, for example, linear and plane indivisibles. In this paper, I will complement this recent trend by focusing on how Cavalieri manipulates geometrical objects. In particular, I will investigate one fundamental activity, namely, superposition of geometrical objects. In Cavalieri’s practice, superposition is a means of both manipulating geometrical objects and drawing inferences. Finally, I will suggest that an integrated approach, namely, one which strives to understand both objects and activities, can illuminate the history of mathematics.     

Characterization of the role of the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer’s disease

Alzheimer’s disease (AD) is by far the most commonly diagnosed dementia, and despite multiple efforts, there are still no effective drugs available for its treatment. One strategy that deserves to be pursued is to alter the expression and/or physiological action of endogenous proteins instead of administering exogenous factors. In this study, we intend to characterize the roles of the antioxidant, anti-inflammatory, and heavy-metal binding proteins, metallothionein-1?+?2 (MT1?+?2), in a mouse model of Alzheimer’s disease, Tg2576 mice. Contrary to expectations, MT1?+?2-deficiency rescued partially the human amyloid precursor protein-induced changes in mortality and body weight in a gender-dependent manner. On the other hand, amyloid plaque burden was decreased in the cortex and hippocampus in both sexes, while the amyloid cascade, neuroinflammation, and behavior were affected in the absence of MT1?+?2 in a complex manner. These results highlight that the control of the endogenous production and/or action of MT1?+?2 could represent a powerful therapeutic target in AD.     

Nutrigenomics in the whole-genome scanning era: Crohn’s disease as example

Nutrigenomics has the potential to tailor diets to optimize health, based on knowledge of key genetic polymorphisms. Identification of candidate genes is often based on a priori knowledge of disease processes. However, genome-wide association methods are not only validating previously identified genes and polymorphisms, but also revealing new gene-disease associations not anticipated from prior knowledge. In Crohn’s disease (CD), such studies not only confirm the importance of caspase-activated recruitment domain 15 and major histocompatability complex II molecules, but also reveal strong associations with the proinflammatory cytokine interleukin-23 receptor and autophagy-related 16-like gene. Genes identified to date in CD can be linked into two interrelated pathways: receptor-mediated cytokine induction or autophagocytosis. New genomic technologies need to be matched with innovative methodologies to characterize the likely impact of foods and to take the field to another dimension of value for human diet development and optimized health. Received 2 July 2007; received after revision 31 July 2007; accepted 29 August 2007     

Synaptic dysfunction in Huntington’s disease: a new perspective

Huntington’s disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.Received 2 March 2005; received after revision 13 April 2005; accepted 19 April 2005     

On the equivalence of Goodman’s and Hempel’s paradoxes

Historically, Nelson Goodman’s paradox involving the predicates ‘grue’ and ‘bleen’ has been taken to furnish a serious blow to Carl Hempel’s theory of confirmation in particular and to purely formal theories of confirmation in general. In this paper, I argue that Goodman’s paradox is no more serious of a threat to Hempel’s theory of confirmation than is Hempel’s own paradox of the ravens. I proceed by developing a suggestion from R. D. Rosenkrantz into an argument for the conclusion that these paradoxes are, in fact, equivalent. My argument, if successful, is of both historical and philosophical interest. Goodman himself maintained that Hempel’s theory of confirmation was capable of handling the paradox of the ravens. And Hempel eventually conceded that Goodman’s paradox showed that there could be no adequate, purely syntactical theory of confirmation. The conclusion of my argument entails, by contrast, that Hempel’s theory of confirmation is incapable of handling Goodman’s paradox if and only if it is incapable of handling the paradox of the ravens. It also entails that for any adequate solution to one of these paradoxes, there is a corresponding and equally adequate solution to the other.     

Einstein’s quantum theory of the monatomic ideal gas: non-statistical arguments for a new statistics

In this article, we analyze the third of three papers, in which Einstein presented his quantum theory of the ideal gas of 1924–1925. Although it failed to attract the attention of Einstein’s contemporaries and although also today very few commentators refer to it, we argue for its significance in the context of Einstein’s quantum researches. It contains an attempt to extend and exhaust the characterization of the monatomic ideal gas without appealing to combinatorics. Its ambiguities illustrate Einstein’s confusion with his initial success in extending Bose’s results and in realizing the consequences of what later came to be called Bose–Einstein statistics. We discuss Einstein’s motivation for writing a non-combinatorial paper, partly in response to criticism by his friend Ehrenfest, and we paraphrase its content. Its arguments are based on Einstein’s belief in the complete analogy between the thermodynamics of light quanta and of material particles and invoke considerations of adiabatic transformations as well as of dimensional analysis. These techniques were well known to Einstein from earlier work on Wien’s displacement law, Planck’s radiation theory and the specific heat of solids. We also investigate the possible role of Ehrenfest in the gestation of the theory.     

Variations on a theme: Clifford’s parallelism in elliptic space

In 1873, W. K. Clifford introduced a notion of parallelism in the three-dimensional elliptic space that, quite surprisingly, exhibits almost all properties of Euclidean parallelism in ordinary space. The purpose of this paper is to describe the genesis of this notion in Clifford’s works and to provide a historical analysis of its reception in the investigations of F. Klein, L. Bianchi, G. Fubini, and E. Bortolotti. Special emphasis is placed upon the important role that Clifford’s parallelism played in the development of the theory of connections.     

The story of ‘Scientist: The Story of a Word’

This examination of an important paper by Sydney Ross is the first in a projected series of occasional reflections on ‘Annals of Science Classic Papers’ that have had enduring utility within the field of history of science and beyond. First the messages of the paper are examined, some well known but others, particularly Ross's own contemporary concerns about the use of the word ‘scientist’, less so. The varied uses made of the paper by scholars are then traced before Ross's biography is examined in order to try to understand how a figure professionally marginal to the field of history of science came to write such a significant piece. Ross’s interest in the topic appears to have been informed by a romantically tinged scientific progressivism and a deep concern with the importance of linguistic precision in science and in public affairs. The inspirations of the author and the interests of his audience have been only partially aligned, but the paper's insights remain of broad historical interest and have wider ramifications since the denotation ‘scientist’ and its proper application are much debated today in contests over the authority of science.     

Neurobiology and neuroimmunology of Tourette’s syndrome: an update

Tourettes syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourettes syndrome. Moreover, Tourettes syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourettes syndrome. We conclude that Tourettes syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.Received 12 August 2003; received after revision 8 October 2003; accepted 31 October 2003