Accumulation of cadmium in near-isogenic lines of durum wheat (Triticum turgidum L. var durum): the role of transpiration.

Concentrations of cadmium in the grain of durum wheat (Triticum turgidum L. var durum) are often above the internationally acceptable limit of 0.2 mg kg(-1). Cultivars that vary in concentrations of cadmium in the grain have been identified but the physiology behind differential accumulation has not been determined. Three pairs of near-isogenic lines (isolines) of durum wheat that vary in aboveground cadmium accumulation (8982-TL 'high' and 'low', W9260-BC 'high' and 'low', and W9261-BG 'high' and 'low') were used to test the hypothesis that the greater amounts of cadmium in shoots of the 'high' isolines are correlated with greater volumes of water transpired. In general, cadmium content was positively correlated with transpiration only in the 'low' isolines. Although shoots of the 'high' isolines of W9260-BC and W9261-BG contained higher concentrations of cadmium than did their corresponding 'low' isolines, they did not transpire larger volumes of water. In addition, isolines of 8982-TL transpired less water than did the other pairs of isolines yet both 'high' and 'low' isolines of 8982-TL contained higher amounts of cadmium than did the other pairs. The difference between 'high' and 'low' isolines appears to be related to the relative contribution of transpiration to cadmium translocation to the shoot. Increased transpiration was associated with increased cadmium content in the 'low' isolines but in the 'high' isolines increased cadmium in the shoot occurred independently of the volume of water transpired.

Benzodioxocin-3-ones and N-acyl-3-amino-3-buten-2-ones: novel classes of cathepsin K cysteine protease inhibitors.

The design, synthesis, enzymologic, and protein mass spectrometric characterization of benzodioxocin-3-one and N-acyl-3-amino-3-buten-2-one inhibitors of the cysteine protease cathepsin K are described. The benzodioxocin-3-one ring system is chemically unstable giving rise to a mixture of N-acyl-3-amino-3-buten-2-one and hemiketals. This mixture of N-acyl-3-amino-3-buten-2-one and hemiketals potently inhibits recombinant, human cathepsin K (IC50 = 36 nM) by a time-independent, irreversible mechanism. Formation of a covalent adduct between cathepsin K and inhibitor has been confirmed by mass spectrometry.

Azepanone-based inhibitors of human and rat cathepsin K.

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.

Cyclic ketone inhibitors of the cysteine protease cathepsin K.

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.

Myrtaceae revisited: a reassessment of infrafamilial groups.

Cladistic analyses are presented of matK sequence data as well as a nonmolecular database for an identical set of exemplar species chosen to represent the core genera or groups of genera in Myrtaceae. Eleven robust clades are recognized on the molecular data. Polyphyly of the previously recognized Metrosideros and Leptospermum alliances is confirmed, and several smaller informal taxonomic groupings are recognized from among the members of the former alliance, i.e., the Tristania, Tristaniopsis, Metrosideros, and Lophostemon groups. The nonmolecular analysis provides only limited resolution of relationships. A degree of congruence exists between the two analyses in that two separate fleshy-fruited clades, the Acmena and Myrtoid groups, are identified, as are the Eucalypt and Tristania groups, and Psiloxylon and Heteropyxis are the first lineages to diverge in both analyses. A combined analysis recognized all 11 clades that received strong support from the molecular data. A high level of homoplasy is revealed in many of the nonmolecular characters when they are examined against the combined estimate of phylogeny.

Cystoid macular edema.

Cystoid macular edema (CME) may develop in association with a wide variety of ocular conditions. It is the result of cystic accumulation of extracellular intraretinal fluid in the outer plexiform and inner nuclear layers of the retina, as a result of breakdown of the blood-retinal barrier. It is most common following intraocular surgery, and in patients with venous occlusive disease, diabetic retinopathy, and posterior segment inflammatory conditions. A variety of approaches to the treatment of CME have been attempted, with a variable degree of success. These options have included topical and oral steroids, nonsteroidal anti-inflammatory agents, and laser photocoagulation treatment. The exact cause of CME and the effective treatment of this condition have remained elusive.