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Gamma-secretase is an intramembrane-cleaving protease responsible for the final proteolytic event in the production of the amyloid-beta peptides (Abeta) implicated in Alzheimer's disease (AD). Inhibition of gamma-secretase activity is thus an attractive therapeutic strategy to slow down the pathogenesis of AD. Drugs often target more than one biomolecule because of conserved 3-dimensional structures in prospective protein binding sites. We have capitalized on this phenomenon of nature to identify new gamma-secretase inhibitors. Here we show that 2-hydroxy naphthyl derivatives, a previously identified subclass of NAD(+) analog inhibitors of sirtuin 2 (SIRT2), are direct gamma-secretase inhibitors. Subsequent structure-activity relationship studies further showed that 2-hydroxy-1-naphthaldehyde is the minimal pharmacophore for gamma-secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide-binding site (NBS) shared by the gamma-secretase subunit presenilin-1 C-terminal fragment (PS1-CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3-dimensional structure of gamma-secretase is beyond our knowledge, we took advantage of the known crystal structure of human JAK3 to model the NBS of the PS1-CTF, which includes the catalytic residue D385. Our results suggest that the flexible PS1-CTF (381)LGLG(384) loop comprises a substrate-docking site capable of recognizing specifically different gamma-secretase substrates.

Approximately 10,000 legal-sized male snow crabs Chionoecetes opilio were tagged and released on the commercial fishing grounds of Bonavista Bay between 1979 and 1982 inclusive, The distance that the snow crabs traveled, as determined from 4,255 recaptures, ranged from 0.6 to 74.1 km (mean, 10.7 km; median, 8.5 km). Snow crabs appeared to remain within Bonavista Bay: there was no observed movement to adjacent commercial crab-fishing areas over periods of up to 5 years. The practice of managing the fishery as a discrete unit appears to be warranted.

Altogether, 1,591 commercial-sized (≥95 mm carapace width) male snow crabs were tagged and released in soft-shelled condition onto the commercial crab grounds of Bonavista Bay, Newfoundland, during August 1984. Between September and December 1984, 68% of those animals released were recaptured by commercial crab fishermen. Among those crabs recaptured 31–60 d after release, 32.8% had recovered to a hard-shelled condition. The hard-shelled condition increased to 96% for crabs at large for 76–90 d and was virtually 100% for those at large for more than 90 d.

By means of a gel filtration technique it is shown that plutonium and americium differ in their mode of binding to two glycoproteins isolated from bovine cortical bone. Plutonium binds more strongly than americium, plutonium binding is maximal at pH 6 and americium at pH 8, and sialic acid is involved in the binding of plutonium but not americium. The mechanisms by which these elements bind to glycoproteins in vitro are discussed.