DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice

Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis.     

The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.     

Composition and abundance of periphyton and aquatic insects in Sierra Nevada, California, stream

The species composition of periphyton and benthic insect communities and abundances of common taxa (&;gt;0.1&;#37; of individuals) were examined during snow-free months in Convict Creek, a permanent snowmelt- and spring-fed stream in the Sierra Nevada of California. The communities were highly diverse. The most abundant taxa in the periphyton were diatoms ( Achnanthes minutissima, Cocconeis placentula lineata, Cymbella microcephala, C. sinuata, Fragilaria construens, F. crotonensis , Navicula spp., Synedra acus , and S. rumpens ), except in late spring and summer when several seasonal blue-green algae ( Chamaesiphon incrustans, Lyngbya spp. and Oscillatoria spp.) are at their maximum densities. Most common periphyton taxa vary systematically in abundance with season, but relative abundances of taxa also appear to be influenced by streambed scouring and by concentrations of ambient nutrients. Data on population densities and length frequencies of larval and nymphal stages of common benthic insects and occurrences of pupal and adult stages were examined to determine life history patterns. Taxa hatching in winter and spring and abundant as immatures in late spring include ephemeropterans ( Epeorus longimanus, Drunella flavilinea , and Caudatella heterocaudata ), plecopterans ( Calineuria californica, Doroneuria baumanni, and Pteronarcys princeps ) and dipterans ( Cryptolabis sp.). Common taxa hatching in late spring or summer are the plecopteran Malenka ( californica? ) and the trichopterans Arctopsyche grandis and Rhyacophila acropedes . Several bivoltine and multivoltine ephemeropterans ( Baetis devinctus and B. tricaudatus ) and dipterans ( Simulium spp. and Chironomidae) have summer cohorts. Taxa hatching in late summer or autumn and most abundant in autumn include ephemeropterans ( Baetis spp., Ephemerella infrequens, Epeorus dulciana, Ironodes lepidus , and Paraleptophlebia pallipes ), trichopterans ( Hydropsyche oslari, Lepidostoma spp., Glossosoma califica, Micrasema sp., Brachycentrus americanus, Neophylax sp., and Rhyacophila vaccua ) and dipterans ( Antocha monticola, Pericoma sp., and Chironomidae). Major recurring events that may influence life history patterns and structure of the benthic insect community are (1) near-freezing, nighttime winter water temperatures and occasional anchor ice, (2) a prolonged period of high discharge in late spring and early summer (3) a brief summer, and (4) a prolonged period of moderate stream discharge in autumn when the substratum is stable and food is abundant.     

Zoogeographic patterns and faunal change of South Dakota fishes

We summarized historic and recent fish distributions in South Dakota and analyzed fish faunal similarity at 2 spatial scales (geomorphic province and river drainage) for both historic (native) and recent (post-1990) faunas. We quantified zoogeographic patterns between geomorphic provinces and among neighboring river drainages for historic and recent faunas. We also quantified faunal change (species losses and additions) between provinces and among drainages. Ninety-seven fishes were native to South Dakota, but 111 fishes were present in recent collections because 8 native species were missing, and 22 nonnatives were present. There was high β diversity among historic and recent river drainage fish faunas, but there was between 22% and 56% faunal change between periods. Recent faunas were homogenized compared to historic faunas at both provincial and river drainage spatial scales. Patterns of nonnative species establishment were geographically distinct from patterns of native species loss. Most nonnative species additions were in cold-water or human-made habitats of the Great Plains. Most native species declines stemmed from warm water streams of the Central Lowlands and Missouri River valley. Conservation of rare and declining native species and containment of nonnatives are both necessary to preserve historical patterns of fish biodiversity in South Dakota.     

Classification Using Class Cover Catch Digraphs

class cover catch digraphs based on proximity between training observations. Performance comparisons are presented on synthetic and real examples versus k-nearest neighbors, Fisher's linear discriminant and support vector machines. We demonstrate that the proposed semiparametric classifier has performance approaching that of the optimal parametric classifier in cases for which the optimal is available for comparison.     

A large increase in enzyme-substrate affinity by protein engineering

A single point mutation has been engineered in the tyrosyl-tRNA synthetase that improves its affinity (KM) for its substrate ATP by a factor of 100. In the crystal structure of the tyrosyl tRNA synthetase (of Bacillus stearothermophilus), the side-chain hydroxyl of Thr 51 appears to make a weak hydrogen bond with the AMP moiety of the substrate intermediate, tyrosyl adenylate. In the absence of substrate, however, the hydroxyl group should make a strong hydrogen bond with water which would favour dissociation of the enzyme-substrate complex. We have used oligodeoxynucleotide-directed mutagenesis to construct two point mutants at this site: one to remove the hydroxyl group (Thr 51 leads to Ala 51) and the other, in addition, to distort the local polypeptide backbone (Thr 51 leads to Pro 51). We report here that both mutants have increased activity (kcat/KM for ATP) but one mutant (Pro 51) shows a massive 25-fold increase due mainly to a lowered KM for ATP. This demonstrates dramatically the potential of in vitro mutagenesis for improving the affinity of an enzyme for its substrate.