The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future.     

NG-nitro-L-arginine inhibits non-adrenergic, non-cholinergic relaxation in rabbit urethral smooth muscle.

Electrical field stimulation induced a relaxation response in female rabbit urethral smooth muscle strips precontracted with phenylephrine. The relaxation response was inhibited by tetrodotoxin, but not by atropine, propranolol, or hexamethonium. The relaxation response thus results from stimulation of inhibitory non-adrenergic, non-cholinergic nerves. The electrically induced relaxation response was inhibited by an inhibitor of nitric oxide biosynthesis, NG-nitro-L-arginine. This inhibition was overcome by addition of a precursor of nitric oxide, L-arginine. An inhibitor of soluble guanylate cyclase, methylene blue, reduced the relaxation response, and a selective cyclic GMP phosphodiesterase inhibitor, M & B 22948, potentiated the relaxation response. These data indicate that agents which affect the biosynthesis of nitric oxide are associated with the urethral relaxation response evoked by electrical field stimulation, and that cyclic GMP may mediate the relaxation response.     

Reentrant Processing in Intuitive Perception

The process of perception requires not only the brain''s receipt of sensory data but also the meaningful organization of that data in relation to the perceptual experience held in memory. Although it typically results in a conscious percept, the process of perception is not fully conscious. Research on the neural substrates of human visual perception has suggested that regions of limbic cortex, including the medial orbital frontal cortex (mOFC), may contribute to intuitive judgments about perceptual events, such as guessing whether an object might be present in a briefly presented fragmented drawing. Examining dense array measures of cortical electrical activity during a modified Waterloo Gestalt Closure Task, results show, as expected, that activity in medial orbital frontal electrical responses (about 250 ms) was associated with intuitive judgments. Activity in the right temporal-parietal-occipital (TPO) region was found to predict mOFC (∼150 ms) activity and, in turn, was subsequently influenced by the mOFC at a later time (∼300 ms). The initial perception of gist or meaning of a visual stimulus in limbic networks may thus yield reentrant input to the visual areas to influence continued development of the percept. Before perception is completed, the initial representation of gist may support intuitive judgments about the ongoing perceptual process.     

Comparing Competitive Fitness of West Nile Virus Strains in Avian and Mosquito Hosts

Enzootic transmission of West Nile virus (WNV; Flaviviridae, Flavivirus) involves various species of birds and ornithophilic mosquitoes. Single nucleotide substitutions in the WNV genome may impact viral fitness necessary for WNV adaptation and evolution as previously shown for the WN02 genotype. In an effort to study phenotypic change, we developed an in vivo fitness competition model in two biologically relevant hosts for WNV. The House Finch (HOFI; Haemorhous mexicanus) and Culex tarsalis mosquitoes represent moderately susceptible hosts for WNV, are highly abundant in Western North America and frequently are infected with WNV in nature. Herein, we inoculated HOFIs and Cx. tarsalis competitively (dually) and singly with infectious-clone derived viruses of the founding California isolate COAV997-2003 (COAV997-IC), the founding North American isolate NY99 (NY99-IC), and a 2004 field isolate from California (CA-04), and compared the replicative capacities (fitness) of these viruses to a genetically marked virus of COAV997 (COAV997-5nt) by measuring RNA copy numbers. COAV997 and COAV997-5nt exhibited neutral fitness in HOFIs and Cx. tarsalis, and the temperature-sensitive phenotype of COAV997 did not affect replication in HOFIs as none of the infected birds became febrile. The NY99 and CA-04 isolates demonstrated elevated fitness in HOFIs compared to COAV997-5nt, whereas all viruses replicated to similar titers and RNA copies in Cx. tarsalis, and the only fitness differences were related to infection rates. Our data demonstrated that competitive replication allows for the sensitive comparison of fitness differences among two genetically closely related viruses using relevant hosts of WNV while eliminating host-to-host differences. In conclusion, our approach may be helpful in understanding the extent of phenotypic change in fitness associated with genetic changes in WNV.     

Trivial minimization of extra‐steps under dynamic homology

Farris (1983) stated that the rationale of the parsimony criterion was to minimize extra (i.e. non‐minimal) steps. For traditional characters, this is equivalent to minimizing total steps (i.e. length). Under dynamic homology (sensu Wheeler, 2001 ), this identity is broken. Here, it is shown that extra steps (but not total) can be minimized trivially (to zero) for all data sets on all trees when insertion‐deletion events are considered. © The Willi Hennig Society 2011.