Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.     

Identifying distinct classes of bladder carcinoma using microarrays

Bladder cancer is a common malignant disease characterized by frequent recurrences. The stage of disease at diagnosis and the presence of surrounding carcinoma in situ are important in determining the disease course of an affected individual. Despite considerable effort, no accepted immunohistological or molecular markers have been identified to define clinically relevant subsets of bladder cancer. Here we report the identification of clinically relevant subclasses of bladder carcinoma using expression microarray analysis of 40 well characterized bladder tumors. Hierarchical cluster analysis identified three major stages, Ta, T1 and T2-4, with the Ta tumors further classified into subgroups. We built a 32-gene molecular classifier using a cross-validation approach that was able to classify benign and muscle-invasive tumors with close correlation to pathological staging in an independent test set of 68 tumors. The classifier provided new predictive information on disease progression in Ta tumors compared with conventional staging (P < 0.005). To delineate non-recurring Ta tumors from frequently recurring Ta tumors, we analyzed expression patterns in 31 tumors by applying a supervised learning classification methodology, which classified 75% of the samples correctly (P < 0.006). Furthermore, gene expression profiles characterizing each stage and subtype identified their biological properties, producing new potential targets for therapy.     

Notch1 functions as a tumor suppressor in mouse skin

Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.     

200 Jahre Naturforschende Gesellschaft in Zürich

Ohne Zusammenfassung     

Danes commemorating Darwin: apes and evolution at the 1909 anniversary

This article analyses the Danish 1909 celebrations of the centenary of Charles Darwin's birth on 12 February 1809. I argue that the 1909 meetings, lectures and publications devoted to Darwin and his theory of evolution by natural selection can be characterised by ambivalence: on the one hand, tribute to a great man of science who established a new view of nature and, on the other hand, scepticism towards the Darwinian mechanism of natural selection and the wider religious and political implications drawn from his theory. The article examines both professional and popular commemorative activities, focusing primarily on celebratory articles carried in widely circulated magazines and newspapers. I identify three types of interpretations of Darwin's ideas which I characterise as ‘radical’, ‘evangelical’ and ‘safe’ science. These different positions were closely linked to the political and cultural divisions of the periodical press. Moreover, my analysis of the popular press offers a solid basis for asserting that to most people Darwinism was associated with human evolution, primarily the relationship between man and apes, while more sophisticated discussions about the crisis of Darwinism prominent among naturalists played only a secondary role in the public arena. This article demonstrates the value of using newspapers as historical sources when looking for public images of Darwin, popular receptions of Darwinism and representations of science in general.     

Stimulation of cyclo-oxygenase by lidocaine,a pro-lipoperoxidant

Summary Lidocaine, which was recently demonstrated to be a good pro-lipoperoxidant, was tested on in vitro PGs biosynthesis, and on arachidonate-induced arterial hypotension, in the rabbit. In the in vitro experiments, lidocaine alone was a poor stimulant of cyclo-oxygenase, but it enhanced significantly the cyclo-oxygenase activation of uric acid. In the rabbit, lidocaine lowered the i.v. arachidonate dose necessary to obtain a significant drop of blood pressure.