The genomic basis of the Williams – Beuren syndrome

The Williams-Beuren syndrome is a genomic disorder (prevalence: 1/7,500 to 1/20,000), caused by a hemizygous contiguous gene deletion on chromosome 7q11.23. Typical symptoms comprise supravalvular aortic stenosis, mental retardation, overfriendliness and visuospatial impairment. The common deletion sizes range of 1.5–1.8 mega base pairs (Mb), encompassing app. 28 genes. For a few genes, a genotype-phenotype correlation has been established. The best-explored gene within this region is the elastin gene; its haploinsufficiency causes arterial stenosis. The region of the Williams-Beuren syndrome consists of a single copy gene region (~1.2 Mb) flanked by repetitive sequences – Low Copy Repeats (LCR). The deletions arise as a consequence of misalignment of these repetitive sequences during meiosis and a following unequal crossing over due to high similarity of LCRs. This review presents an overview of the Williams-Beuren syndrome region considering the genomic assembly, chromosomal rearrangements and their mechanisms (i.e. deletions, duplications, inversions) and evolutionary and historical aspects. Received 11 July 2008; received after revision 15 October 2008; accepted 16 October 2008     

The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker?

Mammalian thioredoxin reductase (TrxR) is a selenoprotein with three existing isoenzymes (TrxR1, TrxR2, and TrxR3), which is found primarily intracellularly but also in extracellular fluids. The main substrate thioredoxin (Trx) is similarly found (as Trx1 and Trx2) in various intracellular compartments, in blood plasma, and is the cell’s major disulfide reductase. Thioredoxin reductase is necessary as a NADPH-dependent reducing agent in biochemical reactions involving Trx. Genetic and environmental factors like selenium status influence the activity of TrxR. Research shows that the Trx/TrxR system plays a significant role in the physiology of the adipose tissue, in carbohydrate metabolism, insulin production and sensitivity, blood pressure regulation, inflammation, chemotactic activity of macrophages, and atherogenesis. Based on recent research, it has been reported that the modulation of the Trx/TrxR system may be considered as a new target in the management of the metabolic syndrome, insulin resistance, and type 2 diabetes, as well as in the treatment of hypertension and atherosclerosis. In this review evidence about a possible role of this system as a marker of the metabolic syndrome is reported.     

Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.     

The secret of truffles: A steroidal pheromone?

Summary The steroid 5-androst-16-en-3-ol has a pronounced musk-like scent. It is a major constituent of the pheromone of the boar. It occurs also in axillary sweat of men but is devoid of androgenic activity. The presence of this steroid has been demonstrated in truffles (Tuber melanosporum) both by radioimmunoassay and by gas chromatography-mass spectrometry in quantities of 40–60 ng/g fresh material. This offers an explanation for the ability of pigs to detect truffles growing as deep as 1 m under ground.     

The ontology of quantum field theory: Structural realism vindicated?

In this paper I elicit a prediction from structural realism and compare it, not to a historical case, but to a contemporary scientific theory. If structural realism is correct, then we should expect physics to develop theories that fail to provide an ontology of the sort sought by traditional realists. If structure alone is responsible for instrumental success, we should expect surplus ontology to be eliminated. Quantum field theory (QFT) provides the framework for some of the best confirmed theories in science, but debates over its ontology are vexed. Rather than taking a stand on these matters, the structural realist can embrace QFT as an example of just the kind of theory SR should lead us to expect. Yet, it is not clear that QFT meets the structuralist's positive expectation by providing a structure for the world. In particular, the problem of unitarily inequivalent representations threatens to undermine the possibility of QFT providing a unique structure for the world. In response to this problem, I suggest that the structuralist should endorse pluralism about structure.     

The opposed influences ofβ-adrenergic stimulation and adenosine on the frequency-force relationship of isolated left atria of guinea-pigs

Summary The normal frequency-force relationship of left guinea-pig atria can be largely suspended when strong -adrenergic stimulation by orciprenaline is antagonized by the negative inotropic effect of adenosine, so that contraction amplitude is nearly equal at an intermediate level over a wide range of stimulation rates. Curves obtained with a new method for recording continuous frequency-force loops are presented.     

The plasmin–antiplasmin system: structural and functional aspects

The plasmin–antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α₂-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α₂-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α₂-antiplasmin, the plasmin–antiplasmin system is also regulated by the general protease inhibitor α₂-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.     

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.     

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.     

The ‘Chemistry of Space’: The Sources of Hermann Grassmann's Scientific Achievements

Albert Lewis's article (Annals of Science, 1977) analysing the influence of Friedrich Schleiermacher on Hermann Grassmann, stimulated many different studies on the founder of n-dimensional outer algebra.

Following a brief outline of the various, sometimes diverging, analyses of Grassmann's creative thinking, new research is presented which confirms Lewis's original contribution and widens it considerably. It will be shown that:

i.?Grassmann, although a self-taught mathematician, was at the centre of a hitherto understated intellectual trend, which was defining for Germany. Initiated by Pestalozzi's concept of elementary mathematical education and culminating in the modern mathematics of the late 19th Century, it was reflected in the contributions of Grassmann, Riemann, Jacobi and Eisenstein.

ii.?Hermann Grassmann, his father Justus, and his brother Robert were all demonstrably influenced by Schleiermacher's dialectic; however the two brothers responded to it in very different ways.

iii.?Whilst the more philosophical parts of Hermann's 1844 Extension Theory are characterised by the influence of Schleiermacher and also by the mathematical knowledge of his father, the entire development of this work is the unfolding of a single idea based on the father's interpretation of combinatorial multiplication as a ‘chemical conjunction‘, which was developed largely dialectically by Hermann.     

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.     

The phenocopy concept: Illusion or reality?

Zusammenfassung Verfasser bespricht den Begriff Phänokopie und dessen Grenzen. Er kommt zum Schluss, dieser Begriff sei nützlich, sofern er sich auf experimentell produzierte Phänokopien bezieht, die mit den Erbphänotypen identisch oder ihnen sehr ähnlich sind und deren Entwicklungsgang zum mindesten teilweise mit demjenigen homologer Mutanten übereinstimmt.     

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     

The urokinase receptor: a ligand or a receptor? Story of a sociable molecule

In this last decade, the structure and functions of the receptor for the urokinase-type plasminogen activator have been extensively studied and characterized. This interesting receptor plays a key role in cell adhesion, migration and proliferation. It was identified 20 years ago as the specific cell-surface molecule that could bind and concentrate urokinase on the cell membrane, thus initiating the proteolytic cascade promoted by the activation of plasminogen. The identification of new extracellular ligands, such as vitronectin, and of cell-surface interactors, such as integrins and fMet-Leu-Phe receptors, shed new light on its possible roles, totally independent of the enzymatic properties of its ligand. uPAR ligands and interactors and the functional consequences of the multiple binding capability of this intriguing receptor are reviewed here. Received 19 September 2005; received after revision 4 December 2005; accepted 6 December 2005     

The semenogelins: proteins with functions beyond reproduction?

The coagulum proteins of human semen, semenogelins I and II, are secreted in abundance by the seminal vesicles. Their function in reproduction is poorly understood as they are rapidly degraded in ejaculated semen. However, more recent results indicate that it is time to put the semenogelins in a broader physiological perspective that goes beyond reproduction and fertility. Received 21 June 2006; received after revision 16 August 2006; accepted 28 September 2006