Involvement of Cyclic GMP Phosphodiesterase Activator in an Hereditary Retinal Degeneration

CYCLIC NUCLEOTIDES mediate many aspects of normal cellular metabolism; thus, degradation as well as synthesis of these intracellular mediators must be strictly regulated. Phosphodiesterase (PDE), the enzyme of cyclic nucleotide catabolism, is present in mammalian tissues in multiple forms, which differ in substrate specificity, kinetic characteristics and sub-cellular localisation. Moreover, a calcium-dependent protein activator (now called calmodulin) has been characterised that specifically activates at least one of the PDE types although other types of PDE are known to be activator independent. Thus, several mechanisms are present in vivo which allow strict control of PDE. A unique cyclic GMP-PDE is compartmentalised in the outer segments of retinal photoreceptor cells; its activity is low in the dark-adapted state but increases dramatically on light adaptation. The resulting drop in cyclic GMP content could serve as a chemical ‘signal’ in the normal visual process. However, despite much investigation of various cyclic nucleotide systems, no definitive information has been obtained which clearly links a disorder of cyclic nucleotide metabolism with a disease process elsewhere than in retina. We have recently presented preliminary evidence that an abnormality in cyclic GMP metabolism could be present in the retinas of Irish setter dogs with inherited rod–cone dysplasia that could lead to greatly increased cyclic GMP content, as had been reported in mice with inherited retinal degeneration. We now report that the basic defect in the disease seems to be a failure to switch PDE type and a concomitant decrease in protein activator concentration early in postnatal development, at the time of photoreceptor differentiation

Magma genesis in the northern Lau Basin, S.W. Pacific

The northern Lau Basin contains the northeastern-most part of the Tonga arc-basin system. Volcanic rocks associated with the recent-arc have been sampled from Tafahi and Niuatoputapu, and young basalts «1.5Ma) have been dredged from Northern Lau Spreading Centre (NLSC), the northeastern limb of the King's Triple Junction. The 1982 'Kallisto' cruise dredged two ophiolite sections, one containing boninitic, and the other tholeiitic, lavas, from the inner wall of the northern Tonga trench. The magma genesis of these lava suites is related to the structural and geochemical controls imposed during the tectonic evolution of the region. The geochemical controls result from processes related to the mantle dynamics in the northern Lau Basin, and to along-trench variations and the degree of influence of the subduction component. The lavas associated with the Central Lau Spreading Centre are derived from the Lau Basin mantle reservoir, which has Indian MORB mantle (!MM) isotopic characteristics. This reservoir has been present under the region since early-arc magmatism, as indicated by the trace elements and !MM isotopic signatures of the tholeiitic lavas from the eastern ophiolite section, and Eocene lavas from 'Eua. A reservoir with the geochemical characteristics of residual Samoan plume mantle underlies the northern Lau Basin. This mantle has been influxing through the rip in the Pacific plate, at the northern termination of the Tonga trench, since the Lau Basin began to open « 6Ma), as a result of processes relating to subduction roll-back. The north Tongan boninites, the lavas from Tafahi and Niuatoputapu have residual plume mantle sources. However, prior to the opening of the Lau Basin, the proto-Tonga trench formed a barrier to this influx, and therefore, the influence of the plume cannot be detected in lavas associated with the early-arc, such as the tholeiites from one of the ophiolite sections and the Eocene lavas from 'Bua. The variations in the trace element and Pb isotopic compositions of the lavas from the Northern Lau Spreading Centre indicate that mixing has occurred between Lau Basin and residual plume mantle end-members in the central northern Lau Basin. The residual plume mantle sources of the north Tongan boninites and the lavas from Tafahi, Niuatoputapu and the Tofua arc have been enriched by a subduction component, the characteristics of which are enrichment in Lll..E, Ph ± LREE. In the south, the subduction component is made up of fluids derived from subducted Pacific altered oceanic crust and pelagic sediments. However, in the north, it is comprised predominantly of fluids derived from Pacific volcanogenic sediments, with a contribution from altered oceanic crust and possibly subducted plume crust

Naiveté, projection bias, and habit formation in gym attendance

We implement a gym-attendance incentive intervention and elicit subjects' predictions of their postintervention attendance. We find that subjects greatly overpredict future attendance, which we interpret as evidence of partial naiveté with respect to present bias. We find a significant postintervention attendance increase, which we interpret as habit formation, and which subjects appear not to predict ex ante. These results are consistent with a model of projection bias with respect to habit formation. Neither the intervention incentives, nor the small posttreatment incentives involved in our elicitation mechanism, appear to crowd out existing intrinsic motivation. The combination of naiveté and projection bias in gym attendance can help to explain limited take-up of commitment devices by dynamically inconsistent agents, and points to new forms of contracts. Alternative explanations of our results are discussed

Working Men's Co-operative Organizations in Great Britain

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Genetic and Phenotypic Variations of Inherited Retinal Diseases in Dogs: The Power of Within- and Across-Breed Studies

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision