Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.Received 30 November 2004; received after revision 24 January 2005; accepted 5 February 2005     

Marrow mesenchymal stem cells transduced with TPO/FL genes as support for ex vivo expansion of hematopoietic stem/progenitor cells

A new marrow-derived mesenchymal stem cell (hMSC) line that could support expansion of hematopoietic stem/progenitor cells (HSPCs) was developed. Primary hMSCs were infected with retrovirus containing Flt-3 ligand and thrombopoietin genes. CD34+ cells from cord blood were expanded with primary hMSCs or transduced hMSCs. The expansion of total nucleated cells, CD34+ cells and mixed colonies containing erythroid and myeloid cells and megakaryocytes for 2 weeks coculture with transduced hMSCs was remarkably increased. The outputs of long-term culture-initiating cells for 2 and 4 weeks coculture with transduced hMSCs were also largely increased. The expansion rates of HSPCs with transduced hMSCs were unchanged for 6 weeks. In contrast, the expansion rates of HSPCs with primary hMSCs declined drastically through 6 weeks. SCID-repopulating cell expansion with transduced hMSCs for 4 weeks was significantly higher than that of uncultured CD34+ cells and HSPCs expanded with primary hMSCs. Received 21 June 2005; received after revision 30 July 2005; accepted 24 August 2005     

Monosynaptic reflex and natural sleep

Résumé Le réflexe monosynaptique (MSR) du nerf tibial ou du péronier a été observé chez le chat intact en expériences chroniques et non-anesthesié au cours des deux différentes phases du sommeil; la phase de hautvoltage ou des fuseaux et la phase paradoxale de basvoltage.Au cours de cette dernière, le MSR diminue d'amplitude, souvent même disparaît, et le seuil est toujours haut placé.     

Detection and imaging of atmospheric radio flashes from cosmic ray air showers

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.     

Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos

A striking feature of the body plan of a majority of animals is bilateral symmetry. Almost nothing is known about the mechanisms controlling the symmetrical arrangement of the left and right body sides during development. Here we report that blocking the production of retinoic acid (RA) in chicken embryos leads to a desynchronization of somite formation between the two embryonic sides, demonstrated by a shortened left segmented region. This defect is linked to a loss of coordination of the segmentation clock oscillations. The lateralization of this defect led us to investigate the relation between somitogenesis and the left-right asymmetry machinery in RA-deficient embryos. Reversal of the situs in chick or mouse embryos lacking RA results in a reversal of the somitogenesis laterality defect. Our data indicate that RA is important in buffering the lateralizing influence of the left-right machinery, thus permitting synchronization of the development of the two embryonic sides.