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

Synthesis and subcellular fate of proteins encoded by the mouse int-2 (FGF3) gene

The int-2 gene encodes a member of the FGF family and was discovered as a proto-oncogene transcriptionally activated in tumours induced by Mouse Mammary Tumour Virus. Int-2 transcription is rarely detected in adult mouse tissues apart from low levels in brain and testis, but in situ hybridisation has revealed widespread expression during embryogenesis. The predicted int-2 gene product has a molecular mass of 27 kD and a hydrophobic sequence at the N-terminus which acts as a signal peptide for vectorial synthesis into the endoplasmic reticulum. The products have proved difficult to detect in natural sources known to contain int-2 RNA such as mammary tumours and embryo-derived cell lines. Consequently the protein has been characterised by expression of cloned cDNAs in COS-1 cells using an SV40-based plasmid vector, in insect cells infected with recombinant baculoviruses and by translation of synthetic sense RNA in cell-free systems supplemented with canine pancreatic microsomes. These studies identified four major int-2 products ranging in size from 27.5 kD to 31.5 kD which arise by post-translational modification of a 28.5 kD primary translation product. Although int-2 proteins are targeted to the secretory pathway, they have only been detected at very low levels in the medium and the associated extracellular matrix of transfected COS-1 cells. Cell-free translation systems programmed with synthetic int-2 RNA identified an additional N-terminally extended product which initiates from an in-frame CUG codon located upstream of the first AUG. Immunofluorescent staining of transfected COS-1 cells showed that a substantial proportion of this extended product localised in the cell nucleus, while a truncated int-2 protein lacking both the N-terminal extension and the signal peptide was exclusively nuclear. These observations suggested that the signals required for nuclear localisation of int-2 were encoded in the body of the molecule, but only functioned when entry into the secretory pathway was compromised. Two nuclear targeting sequences were identified by mutagenesis. Fusion of these motifs to the cytosolic protein pyruvate kinase did not result in effective nuclear localisation. However chimaeras containing int-2 and hst, an exclusively secreted member of the FGF-family, identified a targeting signal sequence with superficial resemblance to the bipartite nuclear localisation sequence of Xenopus nucleoplasmin. Initiation at alternative codons changes the sub-cellular fate of the protein and in principle provides a means imparting distinct functions upon the different int-2 products. Although a biological activity has yet to be assigned to the nuclear forms, the secreted protein is transforming in a NIH3T3 focus assay. The efficiency of focus formation was augmented by mutations which prevented initiation at the CUG codon or at an upstream AUG in the +1 reading frame, resulting in elevated levels of secreted int-2. Thus transformation was shown to require a high level of int-2 synthesis and secretion. In agreement with these findings, mutations which reduce the efficiency of secretion reduce the focus forming ability of NIH3T3 cells transfected with int-2 cDNAs, substantiating the notion that transformation is effected through an autocrine loop mechanism that involves a cell surface receptor

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

Green Infrastructure Plan for Private Property in Richmond, Virginia.

This plan was developed for the City of Richmond Department of Public Utilities (DPU), researching and identifying methods to increase implementation of green infrastructure throughout the City\u27s private residential properties. Green infrastructure (GI) is a relatively new technique utilized for stormwater management, defined by the Environmental Protection Agency as infrastructure mimicking natural processes of absorbing and storing water during large storm events. The implementation of GI directly contributes to the creation of healthier urban environments and the reduction of water quality problems. This plan provides potential funding sources for future GI programs, zones of opportunity for GI and green investments, in addition to strategies the DPU can implement to increase public awareness and participation in residential GI implementation. The research findings indicate that there is a relationship between historically redlined Richmond communities and priority watersheds throughout the City. It is recommended that this relationship be explored further, and that equity considerations be incorporated into future GI programs and policies

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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