Elastin metabolism during recovery from impaired crosslink formation

Accelerated proteolysis of tropoelastin and elastin occurs in the arteries of chicks rendered nutritionally copper-deficient. The process results in part from decreased elastin crosslinking. Repletion of copper-deficient chicks with copper causes a deposition of elastin that is proteinase resistant. Resistance to proteolysis is conferred within 48 h of dietary copper repletion. Deposition of aorta elastin to near normal values occurs after 3-4 days in copper-repleted chicks. Moreover, elastolysis was enhanced when the content of dehydrolysinonorleucine in elastin was abnormally low. The chemical modification of lysyl residue in elastin by citroconylation, however, did not influence the rate of elastolysis. We have shown previously that tropoelastin messenger RNA activity and synthesis are not influenced by dietary copper deprivation (1986, Biochem. J. 236, 17-23). Rather, as demonstrated herein, the decrease in elastin content in arteries of copper-deficient birds appears to be more the result of enhanced degradation. Restoration of normal crosslinking restores deposition and imparts resistance to elastolysis. Moreover, serum appears to be a good source of elastolytic proteinases when the elastin substrate is partially or abnormally crosslinked.     

Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

A new class of 2,6-disubstituted morpholine N-arylsulfonamide γ-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Aβ levels in Tg CRND8 mice upon oral administration were identified.     

Electron-electron double resonance measurements on xanthine oxidase.

Electron-electron double resonance measurements were carried out on milk xanthine oxidase (xanthine:oxygen oxidoreductase EC 1.2.3.2) and the spectra obtained supported a previous model, based on EPR data, proposing a spin-spin interaction between unpaired electrons associated with Fe-S and Mo. The technique demonstrated that the additional apparently isotropic, splitting in the Mo EPR spectra observed at low temperature is produced by a single site giving two spectra interconverting at a rate consistent with the Fe-S spin lattice relaxation time. Other data concerning the model and the relaxation behaviour of the species are discussed.     

APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway

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Novel palmicolous taxa within Pleosporales: multigene phylogeny and taxonomic circumscription

Palm fungi are highly diverse in the tropical regions of Asia. Recent investigations on these palmicolous fungi have led to the collection of astrosphaeriella-like taxa from Calamus, Caryota, and Licuala species in Thailand (Chiang Rai and Narathiwat provinces) and southwest China (Yunnan Province). This study characterizes fungal taxa, which are new to science, based on morphological examination and concatenated DNA sequence data, to infer their familial relationships. Morphological comparisons reveal six new species, viz. Astrosphaeriellopsis caryotae, Fissuroma calami, F. caryotae, Neoastrosphaeriella sribooniensis, Pithomyces caryotae, and P. licualae.Their similarities and differences to other extant species are discussed. The phylogenetic results indicate that all of these new taxa belong to Aigialaceae and Astrosphaeriellaceae (Pleosporales) and support their establishment. Astrosphaeriellopsis is assigned to Astrosphaeriellaceae and the family is amended in order to accommodate both coelomycetous and hyphomycetous asexual morphs. A generic key is presented for Astrosphaeriellaceae to delimit Astrosphaeriella, Astrosphaeriellopsis, Pteridiospora, and Pithomyces. Asexual morph connections of Pithomyces caryotae and P. licualae are established from axenic cultures derived from single ascospores. DNA-based sequence data supports the establishment of our new species; however, the affinities of Astrosphaeriella tornata to other Astrosphaeriella and Pithomyces species are unclear and warrant further investigations with increased taxon sampling.