Synthesis of thrombin-inhibiting heparin mimetics without side effects

Unwanted side effects of pharmacologically active compounds can usually be eliminated by structural modifications. But the complex heterogeneous structure of the polysaccharide heparin has limited this approach to fragmentation, leading to slightly better-tolerated heparin preparations of low molecular mass. Despite this improvement, heparin-induced thrombocytopaenia (HIT), related to an interaction with platelet factor 4 (PF4) and, to a lesser extent, haemorrhages, remain significant side effects of heparinotherapy. Breakthroughs in oligosaccharide chemistry made possible the total synthesis of the pentasaccharide antithrombin-binding site of heparin. This pentasaccharide represents a new family of potential antithrombotic drugs, devoid of thrombin inhibitory properties, and free of undesired interactions with blood and vessel components. To obtain more potent and well-tolerated antithrombotic drugs, we wished to synthesize heparin mimetics able to inhibit thrombin, that is, longer oligosaccharides. Like thrombin inhibition, undesired interactions are directly correlated to the charge and the size of the molecules, so we had to design structures that were able to discriminate between thrombin and other proteins, particularly PF4. Here we describe the use of multistep converging synthesis to obtain sulphated oligosaccharides that meet these requirements.     

Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting

During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation. Using a chemically modified sialic acid precursor (N-propyl-D: -mannosamine), we inhibited the polysialyltransferase ST8SiaII, the principal enzyme involved in polysialylation during development, at selected developmental time-points. This treatment altered NCAM polysialylation while NCAM expression was not affected. Altered polysialylation resulted in an aberrant mossy fiber projection that formed glutamatergic terminals on pyramidal neurons of the CA1 region in organotypic slice cultures and in vivo. Electrophysiological recordings revealed that the ectopic terminals on CA1 pyramids were functional and displayed characteristics of mossy fiber synapses. Moreover, ultrastructural examination indicated a "mossy fiber synapse"-like morphology. We thus conclude that homeostatic regulation of the amount of synthesized polysialic acid at specific developmental stages is essential for correct synaptic targeting and circuit formation during hippocampal development.     

Unpublished boyle papers relating to scientific method.—I

In the late 1720s, Daniel Turner and James Blondel engaged in a pamphlet dispute over the power of the maternal imagination. Turner accepted the long-standing belief that a pregnant woman's imagination could be transferred to her unborn child, imprinting the foetus with various marks and deformities. Blondel sought to refute this view on rational and anatomical grounds. Two issues repeatedly received these authors' attention: the identity of imagination, and its power in pregnant women; and the process of generation and foetal development. In their discussions of these issues, differences between the authors' acceptance of general medical theories and philosophies became apparent. Blondel invoked Newtonian matter theory, experimental philosophy, and iatro-mechanism, while Turner adhered more to the authority of the Ancients and advocated a more direct role for the Creator as an alternative to mechanism in explaining natural phenomena. Additionally, the authors held differing views of what they regarded as experience. The widespread contemporary interest in their dispute suggests that Turner and Blondel raised the phenomenon of the maternal imagination from an issue of folk belief to a concern of eighteenth-century medicine.     

Joint insolation and ice sheet/CO2 forcing on northern China precipitation during Pliocene warmth

East Asian summer monsoon (EASM) precipitation affects the lives of billions of people and impacts the stability of fragile desert ecosystems in central Asia [1...     

Vertebrate circadian rhythms: Retinal and extraretinal photoreception

Summary ERRs Both the pineal and the SCN are elements of the vertebrate multioscillator system although the relative importance of these 2 areas probably varies between, and possibly within, the different vertebrate classes. Extraretinal photoreception is a universal feature of submammalian vertebrates, and possibly of neonatal mammals, but is absent in adult mammals. Although the pineal systems of sumammalian vertebrates are photosensitive, the pineal system has been directly implicated as an extraocular site for the perception of entraining light cycles only in amphibians. In all other submammalian vertebrates extraretinal entrainment can occur in the absence of the pineal system although it is certainly conceivable that the pineal system may act as an alternate route of photoreception. These extraretinal-extrapineal receptors are located within the brain but the exact location(s) of these receptors within the brain is unknown. The hypothalamus would be likely area for this extraretinal photoreception, however, for several reasons: 1. Neurophysiological studies have identified light sensitive neurons in the frog's hypothalamus⁴³. 2. The avian hypothalamus is a site of photoperiodic photoreception^100–103. 3. The only other light sensitive structures known in vertebrates—the pineal system and the lateral eyes—are all derived embryologically from the hypothalamus. 4. The hypothalamus appears to be the site of a circadian clock and there may be advantages in having the photoreceptors and the clock anatomically close to one another. These considerations, of course, do not exclude the possibility that other brain areas may be involved as well. The reason behind the loss of extraretinal photoreception in mammals is uncertain. The shift to exclusive retinal photoreception in mammals may have been dictated by the extensive reorganization that occurred during the evolution of the mammalian brain. Or, perhaps, the increased size of the mammalian skull and overlying tissue made direct photoreception difficult and necessitated a shift to retinal photoreception. The persistence of extraretinal photoreceptors in submammalian vertebrates, however, underscores their importance in the sensory repertoire of vertebrates.     

Chemical components of the rectal gland secretions of maleDacus cucurbitae,the melon fly

Summary The volatile constituents of the rectal gland secretion of maleDacus cucurbitae have been shown to contain 2-methoxy-N-3-methylbutyl acetamide together with 2 other amides, 3 pyrazine derivatives and 2-ethoxybenzoic acid. Excised male rectal glands have been demonstrated to elicit strong responses from female melon flies.Acknowledgment. We thank Dr P. Howse for valuable discussions and advice.     

Night shift paralysis

Summary 12% of night nurses surveyed claimed to have suffered from a totally incapacitating paralysis that may be related to sleep paralysis, and contribute to impaired levels of safety on the night shift. The incidence of this paralysis is shown to be age-related, largely confined to the early hours of the morning, and to increase over consecutive night shifts.Acknowledgments. We wish to dedicate this paper to Professor Dr Günther Hildebrandt, Director of the Institut für Arbeitsphysiologie und Rehabilitationsforschung, University of Marburg/Lahn in honor of his 60th birthday. We also wish to thank the Nursing Officers and nurses concerned for their help in this study.