Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.     

Suppression of cytophilic antibody (‘arming’ factor) in the sera of patients with prostatic cancer by human seminal plasma

Summary The arming of normal peripheral blood leukocytes (PBL) by cytophilic antibody in the sera of prostatic cancer patients is suppressed by pretreatment of PBL with normal human seminal plasma (HuSP1). Suppression of cytophilic antibody by HuSP1 extends the spectrum of immunologic reactions on which SP1 has an immunosuppressive effect and may provide further insight into the possible role of SP1 in the natural history of prostatic cancer.     

Into the ‘regions of physical and metaphysical chaos’: Maxwell’s scientific metaphysics and natural philosophy of action (agency,determinacy and necessity from theology,moral philosophy and history to mathematics,theory and experiment)

Maxwell’s writings exhibit an enduring preoccupation with the role of metaphysics in the advancement of science, especially the progress of physics. I examine the question of the distinction and the proper relation between physics and metaphysics and the way in which the question relies on key notions that bring together much of Maxwell’s natural philosophy, theoretical and experimental. Previous discussions of his attention to metaphysics have been confined to specific issues and polemics such as conceptions of matter and the problem of free will. I suggest a unifying pattern based on a generalized philosophical perspective and varying expressions, although never a systematic or articulated philosophical doctrine, but at least a theme of action and active powers, natural and human, intellectual and material, with sources and grounds in theology, moral philosophy and historical argument. While science was developing in the direction of professional specialization and alongside the rise of materialism, Maxwell held on to conservative intellectual outlook, but one that included a rich scientific life and held science as part of a rich intellectual, cultural and material life. His philosophical outlook integrated his science with and captured the new Victorian culture of construction and work, political, economic, artistic and engineering.     

‘Natures’ and ‘Laws’: The making of the concept of law of nature – Robert Grosseteste (c. 1168–1253) and Roger Bacon (1214/1220–1292)

Contemporary scholars set the Greek conception of an immanent natural order in opposition to the seventeenth century mechanistic conception of extrinsic laws imposed upon nature from without. By contrast, we argue that in the process of making the concept of law of nature, forms and laws were coherently used in theories of natural causation. We submit that such a combination can be found in the thirteenth century. The heroes of our claim are Robert Grosseteste who turned the idea of corporeal form into the common feature of matter, and Roger Bacon who described the effects of that common feature. Bacon detached the explanatory principle from matter and rendered it independent and therefore external to natural substances. Our plausibility argument, anchored in close reading of the relevant texts, facilitates a coherent conception of both ‘natures’ and ‘laws’.     

Sea urchin elongation factor 1δ (EF1δ) and evidence for cell cycle-directed localization changes of a sub-fraction of the protein at M phase

Eukaryotic elongation factor 1 (eEF1) is a translational multimolecular complex reported in higher eukaryotes to be a target of CDK1/cyclin B, the universal regulator of M phase, but whose role in the cell cycle remains to be determined. A specific polyclonal antibody was produced and used to characterize the delta subunit of sea urchin elongation factor 1 (SgEF1) in early embryos, a powerful model for investigating cell cycle regulation. The SgEF1 protein was present in unfertilized eggs as two isoforms of 35 and 37 kDa, issued from two different mRNAs. The two canonical eEF1 partners, eEF1 and eEF1, were shown to co-immunoprecipitate with the SgEF1 isoforms. Both isoforms were associated in a macromolecular complex, which resolved upon gel filtration chromatography at a molecular weight > 400 kDa, suggesting association with other yet unidentified partners. After fertilization, the amount as well as the ratio of both SgEF1 isoforms remained constant during the first cell division as judged by Western blotting. Immunofluorescence analysis showed that a pool of the protein concentrated as a ring at the embryo nuclear location around the period of nuclear envelope breakdown and was visualized later as two large spheres around the mitotic spindle poles. Thus, the eEF1 protein shows cell cycle-specific localization changes in sea urchin embryos.Received 27 May 2003; received after revision 1 July 2003; accepted 4 July 2003     

Helix H1 of the prion protein is rather stable against environmental perturbations: molecular dynamics of mutation and deletion variants of PrP(90–231)

We need to understand the underlying factors that promote or reverse the amyloid-type structure of the prion protein (PrP). In an earlier study, we showed that mutations within the first strand can extend the short sheet in the normal protein into a larger sheet at neutral pH. To determine the impact of the point mutation P102L and the deletion of either the first or the second strand on PrP, we performed further long molecular explicit water dynamics simulations. The trajectories show that all mutations do not exert a uniform effect on the dynamics of the N-terminal tail. The results of the deletion of the two strands confirm the idea that partially unfolded conformations are involved in the structural transition. In the deletion variants, the helices H2 and H3 are disordered, while helix H1 is either fully stable or partially disordered. This finding, consistent with recent spectroscopic analyses on peptides spanning helix H1 and flanking sequences, demonstrates that unfolding of the full domain containing helix H1 is not an early step in PrP interconversion. This result also raises questions regarding a current view of PrP^Sc structure that transforms helix H1 into a sheet conformation.Received 16 December 2003; received after revision 16 January 2004; accepted 21 January 2004     

Reading Gauss in the Computer Age: On the U.S. Reception of Gauss’s Number Theoretical Work (1938–1989)

C.F Gauss’s computational work in number theory attracted renewed interest in the twentieth century due to, on the one hand, the edition of Gauss’s Werke, and, on the other hand, the birth of the digital electronic computer. The involvement of the U.S. American mathematicians Derrick Henry Lehmer and Daniel Shanks with Gauss’s work is analysed, especially their continuation of work on topics as arccotangents, factors of n ² + a ², composition of binary quadratic forms. In general, this strand in Gauss’s reception is part of a more general phenomenon, i.e. the influence of the computer on mathematics and one of its effects, the reappraisal of mathematical exploration. I would like to thank the Alexander-von-Humboldt-Stiftung for funding this research. For their comments I would like to thank Catherine Goldstein, Norbert Schappacher and especially John Brillhart.     

For the Glory of Athens: Xenophon’s Hipparchikos <Logos>, a technical treatise and instruction manual on ideal leadership

Xenophon’s Peri hippikes <technees>, “On Horsemanship,” and the Hipparchikos <logos>, “the Cavalry Commander”, writings which can be regarded as technical works with a didactic purpose, are almost unknown. Xenophon was interested in problems of leadership and the exercise of power (For the titles of the both writings and the analogous supplementary terms “technees” and “logos” compare Breitenbach, 1966, 1761. Angled brackets are used by modern editors of ancient texts as text-critical signs and are inserted here because “peri hippikes” and “hipparchikos” are adjectives and cannot stand alone; “technees” and “logos” are supplied as absent, but implied, substantives. The conventional signs “<>” clarify this supplementary act for the modern reader.). The “Cavalry Commander” (ca. 365 B.C.) intended for the instruction of potential hipparchs (calvary commanders) is simultaneously political and didactic and technical; in this text, categories of leadership that had been developed in earlier works are combined in a powerful manner. Xenophon constructed “leaders” as exempla (“examples”) of correct behaviour; military and political theory are synthesised. The Hipparchikos logos, as a didactic work, aims to produce specialists who master their techné (“art” or “skill”), to develop their ideal qualities. Both texts are directed at an Athenian society, in which the cavalry had lost their significance and pride as a result of recent political turbulence. Xenophon hoped to reform the cavalry for the benefit of Athens. The basic question of the didactic work is: how can I become the best hipparch, how can I go beyond simply filling the office, and instead develop it for the well-being of the polis and thus serve the city? The art of leadership consists in dealing with subordinates in such a manner that they obey and follow voluntarily—still an innovative and modern approach today.     

‘… not fundamental in a state of full civilization’: The Sociedad Astronómica de Barcelona (1910–1921) and its Popularization Programme

Scrutinizing the main activities of the Sociedad Astronómica de Barcelona (SAB), a scientific society that was founded in 1910 and lasted until 1921, this paper analyses how and why its members disseminated astronomy to society at large. Inspired by Camille Flammarion (1842–1925), and with a strong amateur character, the programme of the SAB raised interest among academic scientists, politicians, priests, navy officers, educated audiences, and positivist anticlerical writers. It rapidly conquered the public sphere through well-attended lectures, exhibitions, observations, and publications. In the context of an industrial city, which at that time was suffering serious social tensions, the popularization of astronomy transcended social and cultural boundaries. It created common ground between expert and lay knowledge, science and art, the ‘natural’ and the ‘social’, and between science and religion. In addition, it was considered as one of the only possible ways to raise the scientific level of a country such as Spain, which at that time perceived itself as peripheral, even backward, in terms of mainstream innovations in science and technology.