The meaning of πλασμαтιкό<Emphasis Type="Italic">ν</Emphasis> in Diophantus’ <Emphasis Type="Italic">Arithmetica</Emphasis>

Three problems in book I of Diophantus’ Arithmetica contain the adjective plasmatikon, that appears to qualify an implicit reference to some theorems in Elements, book II. The translation and meaning of the adjective sparked a long-lasting controversy that has become a nonnegligible aspect of the debate about the possibility of interpreting Diophantus’ approach and, more generally, Greek mathematics in algebraic terms. The correct interpretation of the word, a technical term in the Greek rhetorical tradition that perfectly fits the context in which it is inserted in the Arithmetica, entails that Diophantus’ text contained no (implicit) reference to Euclid’s Elements. The clause containing the adjective turns out to be a later interpolation, that cannot be used to support any algebraic interpretation of the Arithmetica.     

<Emphasis Type="Italic">Ginkgo biloba</Emphasis> extract EGb<Superscript>®</Superscript> 761 increases endothelial nitric oxide production <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>

Beneficial effects of Ginkgo biloba on peripheral arterial occlusive disease have been repeatedly shown in clinical trials, especially after use of EGb 761, a standardized special extract. Since the underlying mechanisms are widely unknown, we aimed to elucidate the molecular basis on which EGb 761 protects against endothelial dysfunction in vitro and in vivo. Application of therapeutically feasible doses of EGb 761 for 48 h caused endothelial nitric oxide (NO) production by increasing endothelial nitric oxide synthase (eNOS) promoter activity and eNOS expression in vitro. Phosphorylation of eNOS at a site typical for Akt (Ser 1177) was acutely enhanced by treatment with EGb 761, as was Akt phosphorylation at Ser 478. Furthermore, the extract caused acute relaxation of isolated aortic rings and NO-dependent reduction of blood pressure in vivo in rats. These influences on eNOS represent a putative molecular basis for the protective cardiovascular properties of EGb 761.     

What leads from <Emphasis Type="Italic">dead-end?</Emphasis>

The 129 mouse strain develops congenital testicular germ cell tumors (TGCTs) at a low frequency. TGCTs in mice resemble the testicular tumors (teratomas) that occur in human infants. The genes that cause these tumors in 129 have not been identified. The defect at the Ter locus increases TGCT incidence such that 94% of 129-Ter/Ter males develop TGCTs. The primary effect of the Ter mutation is progressive loss of primordial germ cells (PGCs) during embryonic development. This results in sterility in adult Ter/Ter mice on all mouse strain backgrounds. However, on the 129 background, Ter causes tumor development in addition to sterility. Therefore, Ter acts as a modifier of 129-derived TGCT susceptibility genes. Ter was identified to be a mutation that inactivates the Dead-end1 (Dnd1) gene. In this perspective, I discuss the possible areas of future investigations to elucidate the mechanism of TGCT development due to Dnd1 inactivation. Received 29 September 2006; received after revision 29 January 2007; accepted 19 February 2007     

The Role of Geometrical Construction in Theodosius’s <Emphasis Type="Italic">Spherics</Emphasis>

This paper is a contribution to our understanding of the constructive nature of Greek geometry. By studying the role of constructive processes in Theodoius’s Spherics, we uncover a difference in the function of constructions and problems in the deductive framework of Greek mathematics. In particular, we show that geometric problems originated in the practical issues involved in actually making diagrams, whereas constructions are abstractions of these processes that are used to introduce objects not given at the outset, so that their properties can be used in the argument. We conclude by discussing, more generally, ancient Greek interests in the practical methods of producing diagrams.     

Mean Motions in Ptolemy’s <Emphasis Type="Italic">Planetary Hypotheses</Emphasis>

In the Planetary Hypotheses, Ptolemy summarizes the planetary models that he discusses in great detail in the Almagest, but he changes the mean motions to account for more prolonged comparison of observations. He gives the mean motions in two different forms: first, in terms of ‘simple, unmixed’ periods and next, in terms of ‘particular, complex’ periods, which are approximations to linear combinations of the simple periods. As a consequence, all of the epoch values for the Moon and the planets are different at era Philip. This is in part a consequence of the changes in the mean motions and in part due to changes in Ptolemy’s time in the anomaly, but not the longitude or latitude, of the Moon, the mean longitude of Saturn and Jupiter, but not Mars, and the anomaly of Venus and Mercury, the former a large change, the latter a small one. The pattern of parameter changes we see suggests that the analyses that yielded the Planetary Hypotheses parameters were not the elegant trio analyses of the Almagest but some sort of serial determinations of the parameters based on sequences of independent observations.     

<Emphasis Type="Italic">O</Emphasis>-GlcNAc transferase associates with the MCM2–7 complex and its silencing destabilizes MCM–MCM interactions

O-GlcNAcylation of proteins is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). The homeostasis of O-GlcNAc cycling is regulated during cell cycle progression and is essential for proper cellular division. We previously reported the O-GlcNAcylation of the minichromosome maintenance proteins MCM2, MCM3, MCM6 and MCM7. These proteins belong to the MCM2–7 complex which is crucial for the initiation of DNA replication through its DNA helicase activity. Here we show that the six subunits of MCM2–7 are O-GlcNAcylated and that O-GlcNAcylation of MCM proteins mainly occurs in the chromatin-bound fraction of synchronized human cells. Moreover, we identify stable interaction between OGT and several MCM subunits. We also show that down-regulation of OGT decreases the chromatin binding of MCM2, MCM6 and MCM7 without affecting their steady-state level. Finally, OGT silencing or OGA inhibition destabilizes MCM2/6 and MCM4/7 interactions in the chromatin-enriched fraction. In conclusion, OGT is a new partner of the MCM2–7 complex and O-GlcNAcylation homeostasis might regulate MCM2–7 complex by regulating the chromatin loading of MCM6 and MCM7 and stabilizing MCM/MCM interactions.     

The role of the <Emphasis Type="Italic">ATP2C1</Emphasis> gene in Hailey–Hailey disease

Hailey–Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis, characterized by a chronic course of repeated and exacerbated skin lesions in friction regions. The pathogenic gene of HHD was reported to be the ATPase calcium-transporting type 2C member 1 gene (ATP2C1) located on chromosome 3q21–q24. Its function is to maintain normal intracellular concentrations of Ca²⁺/Mn²⁺ by transporting Ca²⁺/Mn²⁺ into the Golgi apparatus. ATP2C1 gene mutations are reportedly responsible for abnormal cytosolic Ca²⁺/Mn²⁺ levels and the clinical manifestations of HHD. Environmental factors and genetic modifiers may also affect the clinical variability of HHD. This article aims to critically discuss the clinical and pathological features of HHD, differential diagnoses, and genetic and functional studies of the ATP2C1 gene in HHD. Further understanding the role of the ATP2C1 gene in the pathogenesis of HHD by genetic, molecular, and animal studies may contribute to a better clinical diagnosis and provide new strategies for the treatment and prevention of HHD.     

"Add-on" domains of<Emphasis Type="Italic"> Drosophila</Emphasis> β1,4-<Emphasis Type="Italic">N</Emphasis>-acetylgalactosaminyltransferase B in the stem region and its pilot protein

The glycolipid specific Drosophila melanogaster β1,4-N-acetylgalactosaminyltransferase B (β4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI) for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential for palmitoylation in DHHC proteins, is not required for GABPI to interact with β4GalNAcTB. In contrast, the two luminal loops between transmembrane domain 3–4 and 5–6 contain conserved amino acids, which are crucial for activity. Besides the dependence on GABPI, β4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, β4GalNAcTB, thus, requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive GABPI mutants could be rescued by fusion with β4GalNAcTB, indicating their importance in direct GABPI-β4GalNAcTB interaction.     

Between Viète and Descartes: Adriaan van Roomen and the <Emphasis Type="Italic">Mathesis Universalis</Emphasis>

Adriaan van Roomen published an outline of what he called a Mathesis Universalis in 1597. This earned him a well-deserved place in the history of early modern ideas about a universal mathematics which was intended to encompass both geometry and arithmetic and to provide general rules valid for operations involving numbers, geometrical magnitudes, and all other quantities amenable to measurement and calculation. ‘Mathesis Universalis’ (MU) became the most common (though not the only) term for mathematical theories developed with that aim. At some time around 1600 van Roomen composed a new version of his MU, considerably different from the earlier one. This second version was never effectively published and it has not been discussed in detail in the secondary literature before. The text has, however, survived and the two versions are presented and compared in the present article. Sections 1–6 are about the first version of van Roomen’s MU the occasion of its publication (a controversy about Archimedes’ treatise on the circle, Sect. 2), its conceptual context (Sect. 3), its structure (with an overview of its definitions, axioms, and theorems) and its dependence on Clavius’ use of numbers in dealing with both rational and irrational ratios (Sect. 4), the geometrical interpretation of arithmetical operations multiplication and division (Sect. 5), and an analysis of its content in modern terms. In his second version of a MU van Roomen took algebra into account, inspired by Viète’s early treatises; he planned to publish it as part of a new edition of Al-Khwarizmi’s treatise on algebra (Sect. 7). Section 8 describes the conceptual background and the difficulties involved in the merging of algebra and geometry; Sect. 9 summarizes and analyzes the definitions, axioms and theorems of the second version, noting the differences with the first version and tracing the influence of Viète. Section 10 deals with the influence of van Roomen on later discussions of MU, and briefly sketches Descartes’ ideas about MU as expressed in the latter’s Regulae.     

Proposition II (Book I) of Newton’s <Emphasis Type="Italic">Principia</Emphasis>

After preparing the way with comments on evanescent quantities and then Newton’s interpretation of his second law, this study of Proposition II (Book I)— Proposition II Every body that moves in some curved line described in a plane and, by a radius drawn to a point, either unmoving or moving uniformly forward with a rectilinear motion, describes areas around that point proportional to the times, is urged by a centripetal force tending toward that same point. —asks and answers the following questions: When does a version of Proposition II first appear in Newton’s work? What revisions bring that initial version to the final form in the 1726 Principia? What, exactly, does this proposition assert? In particular, what does Newton mean by the motion of a body “urged by a centripetal force”? Does it assert a true mathematical claim? If not, what revision makes it true? Does the demonstration of Proposition II persuade? Is it as convincing, for example, as the most convincing arguments of the Principia? If not, what revisions would make the demonstration more persuasive? What is the importance of Proposition II, to the physics of Book III and the mathematics of Book I?     

Conventions for recreational problems in Fibonacci’s <Emphasis Type="Italic">Liber Abbaci</Emphasis>

Fibonacci’s treatment of so-called recreational problems in his Liber Abbaci has been interpreted as an early episode both in the history of systems of linear equations, and in the history of negative numbers. However, these problems are also interesting in their own right. We discuss some of the conventions which seem to have governed these problems. By considering certain pairs of problems, where one problem is unsolvable and its partner is solvable, we show that Fibonacci went to a significant effort to conform to these conventions. We also examine the methods which he could have used to construct his problems.     

Beta-carotene affects gene expression in lungs of male and female <Emphasis Type="Italic">Bcmo1</Emphasis><Superscript>−/−</Superscript> mice in opposite directions

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 ^−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 ^−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1 ^−/− mice, which had, unlike wild-type (Bcmo1 ^+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.     

<Emphasis Type="Italic">Trichomonas vaginalis</Emphasis> degrades nitric oxide and expresses a flavorubredoxin-like protein: a new pathogenic mechanism?

Besides possessing many physiological roles, nitric oxide (NO) produced by the immune system in infectious diseases has antimicrobial effects. Trichomoniasis, the most widespread non-viral sexually transmitted disease caused by the microaerophilic protist Trichomonas vaginalis, often evolves into a chronic infection, with the parasite able to survive in the microaerobic, NO-enriched vaginal environment. We relate this property to the finding that T. vaginalis degrades NO under anaerobic conditions, as assessed amperometrically. This activity, which is maximal (133 ± 41 nmol NO/10⁸ cells per minute at 20°C) at low NO concentrations ( 1.2 M), was found to be: (i) NADH dependent, (ii) cyanide insensitive and (iii) inhibited by O₂. These features are consistent with those of the Escherichia coli A-type flavoprotein (ATF), recently discovered to be endowed with NO reductase activity. Using antibodies against the ATF from E. coli, a protein band was immunodetected in the parasite grown in a standard medium. If confirmed, the expression of an ATF in eukaryotes suggests that the genes coding for ATFs were transferred during evolution from anaerobic Prokarya to pathogenic protists, to increase their fitness for the microaerobic, parasitic life style. Thus the demonstration of an ATF in T. vaginalis would appear relevant to both pathology and evolutionary biology. Interestingly, genomic analysis has recently demonstrated that Giardia intestinalis and other pathogenic protists have genes coding for ATFs.Received 1 November 2003; received after revision 5 January 2004; accepted 13 January 2004     

The in vivo role of α-mannosidase IIx and its role in processing of <Emphasis Type="Italic">N</Emphasis>-glycans in spermatogenesis

The surfaces of mammalian cells are covered by a variety of carbohydrates linked to proteins and lipids. N-glycans are commonly found carbohydrates in plasma membrane proteins. The structure and biosynthetic pathway of N-glycans have been analyzed extensively. However, functional analysis of cell surface N-glycans is just under way with recent studies of targeted disruption of genes involved in N-glycan synthesis. This review briefly introduces the potential role of processing -mannosidases in N-glycan biosynthesis and recent findings derived from the -mannosidase IIx (MX) gene knockout mouse, which shows male infertility. Thus, the MX gene knockout experiment unveiled a novel function of specific N-glycan, which is N-acetylglucosamine-terminated and fucosylated triantennary structure, in the adhesion between germ cells and Sertoli cells. Analysis of the MX gene knockout mouse is a good example of a multidisciplinary approach leading to a novel discovery in the emerging field of glycobiology.Received 29 November 2002; received after revision 30 December 2002; accepted 20 January 2003     

<Emphasis Type="Italic">Legionella pneumophila</Emphasis> — a human pathogen that co-evolved with fresh water protozoa

The bacterial pathogen Legionella pneumophila is found ubiquitously in fresh water environments where it replicates within protozoan hosts. When inhaled by humans it can replicate within alveolar macrophages and cause a severe pneumonia, Legionnaires disease. Yet much needs to be learned regarding the mechanisms that allow Legionella to modulate host functions to its advantage and the regulatory network governing its intracellular life cycle. The establishment and publication of the complete genome sequences of three clinical L. pneumophila isolates paved the way for major breakthroughs in understanding the biology of L. pneumophila. Based on sequence analysis many new putative virulence factors have been identified foremost among them eukaryotic-like proteins that may be implicated in many different steps of the Legionella life cycle. This review summarizes what is currently known about regulation of the Legionella life cycle and gives insight in the Legionella-specific features as deduced from genome analysis. Received 1 September 2006; received after revision 10 October 2006; accepted 22 November 2006     

<Emphasis Type="Italic">Clostridium difficile</Emphasis>-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum?

Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network.