In vitro cytostatic effect of adenine-arabinoside (Ara-A) and cytosine-arabinoside (Ara-C)

Summary Adenine-arabinoside, a new antiviral drug with questionable bone marrow toxicity, inhibits colony formation by myeloid precursor cells in vitro. Compared to cytosine-arabinoside this cytotoxicity is roughly one third.Supported by grants of the Swiss Cancer League (FOR 101.AK.77.2) and the Swiss Science Foundation (3.3320.74).Acknowledgments. We wish to thank Prof. A. Lévy for support in providing normal bone marrow samples and Miss Beatrice Rubin for skilled technical assistance.     

The virophage as a unique parasite of the giant mimivirus

Viruses are obligate parasites of Eukarya, Archaea and Bacteria. Acanthamoeba polyphaga mimivirus (APMV) is the largest known virus; it grows only in amoeba and is visible under the optical microscope. Mimivirus possesses a 1,185-kilobase double-stranded linear chromosome whose coding capacity is greater than that of numerous bacteria and archaea1, 2, 3. Here we describe an icosahedral small virus, Sputnik, 50 nm in size, found associated with a new strain of APMV. Sputnik cannot multiply in Acanthamoeba castellanii but grows rapidly, after an eclipse phase, in the giant virus factory found in amoebae co-infected with APMV4. Sputnik growth is deleterious to APMV and results in the production of abortive forms and abnormal capsid assembly of the host virus. The Sputnik genome is an 18.343-kilobase circular double-stranded DNA and contains genes that are linked to viruses infecting each of the three domains of life Eukarya, Archaea and Bacteria. Of the 21 predicted protein-coding genes, eight encode proteins with detectable homologues, including three proteins apparently derived from APMV, a homologue of an archaeal virus integrase, a predicted primase-helicase, a packaging ATPase with homologues in bacteriophages and eukaryotic viruses, a distant homologue of bacterial insertion sequence transposase DNA-binding subunit, and a Zn-ribbon protein. The closest homologues of the last four of these proteins were detected in the Global Ocean Survey environmental data set5, suggesting that Sputnik represents a currently unknown family of viruses. Considering its functional analogy with bacteriophages, we classify this virus as a virophage. The virophage could be a vehicle mediating lateral gene transfer between giant viruses.     

Ephrin signalling controls brain size by regulating apoptosis of neural progenitors

Mechanisms controlling brain size include the regulation of neural progenitor cell proliferation, differentiation, survival and migration. Here we show that ephrin-A/EphA receptor signalling plays a key role in controlling the size of the mouse cerebral cortex by regulating cortical progenitor cell apoptosis. In vivo gain of EphA receptor function, achieved through ectopic expression of ephrin-A5 in early cortical progenitors expressing EphA7, caused a transient wave of neural progenitor cell apoptosis, resulting in premature depletion of progenitors and a subsequent dramatic decrease in cortical size. In vitro treatment with soluble ephrin-A ligands similarly induced the rapid death of cultured dissociated cortical progenitors in a caspase-3-dependent manner, thereby confirming a direct effect of ephrin/Eph signalling on apoptotic cascades. Conversely, in vivo loss of EphA function, achieved through EphA7 gene disruption, caused a reduction in apoptosis occurring normally in forebrain neural progenitors, resulting in an increase in cortical size and, in extreme cases, exencephalic forebrain overgrowth. Together, these results identify ephrin/Eph signalling as a physiological trigger for apoptosis that can alter brain size and shape by regulating the number of neural progenitors.     

A sharp lithosphere-asthenosphere boundary imaged beneath eastern North America

Plate tectonic theory hinges on the concept of a relatively rigid lithosphere moving over a weaker asthenosphere, yet the nature of the lithosphere-asthenosphere boundary remains poorly understood. The gradient in seismic velocity that occurs at this boundary is central to constraining the physical and chemical properties that create differences in mechanical strength between the two layers. For example, if the lithosphere is simply a thermal boundary layer that is more rigid owing to colder temperatures, mantle flow models indicate that the velocity gradient at its base would occur over tens of kilometres. In contrast, if the asthenosphere is weak owing to volatile enrichment or the presence of partial melt, the lithosphere-asthenosphere boundary could occur over a much smaller depth range. Here we use converted seismic phases in eastern North America to image a very sharp seismic velocity gradient at the base of the lithosphere-a 3-11 per cent drop in shear-wave velocity over a depth range of 11 km or less at 90-110 km depth. Such a strong, sharp boundary cannot be reconciled with a purely thermal gradient, but could be explained by an asthenosphere that contains a few per cent partial melt or that is enriched in volatiles relative to the lithosphere.     

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.     

Agreement in endpoints from circadian rhythmometry on healthy human beings living on different continents

Zusammenfassung Circadiane Akrophasen — Gipfel der ungefähren 24-h-Periodik — von Blut- und Harnkortikosteroiden, Kalium im Harn, Körpertemperatur, Pulsrate und 2-min-Schätzung wurden mittels elektronischer Anpassung einer Kosinusfunktion vermöge der Methode der kleinsten Quadrate bestimmt. Solche Charakteristika circadianer Rhythmen empfehlen sich als Referenzstandarde dem Mediziner und Biologen durch ihre zufriedenstellende übereinstimmung in Daten von Untersuchungen auf verschiedenen Kontinenten mit zum Teil unterschiedlichen Methoden.     

Knowledge transfer and its contexts

Knowledge transfer across different contexts has become an increasingly prevalent feature of current science. As such, it is a relevant topic also for historians and philosophers of science. This special issue presents a set of papers that study knowledge transfer in various disciplines. The contributions approach the topic from 1) an integrated history and philosophy of science perspective, 2) a systematic philosophical perspective, or 3) a historical perspective. Taken together, they give a broad introduction into the topic and offer a set of conceptual resources for the study of knowledge transfer in multiple contexts.