Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice

Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-beta(1) and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis.     

2-(Anilinomethyl)imidazolines as alpha(1)-adrenoceptor agonists: the identification of alpha(1A) subtype selective 2'-carboxylic acid esters and amides

2-(Anilinomethyl)imidazolines with 2'-esters or 2'-amides are potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The size and shape of the ortho substituent can have significant effects on the potency, efficacy, and subtype selectivity of these 2-(anilinomethyl)imidazolines. alpha(1A)-subtype selective agonists have been identified.     

alpha(1)-Adrenoceptor agonists: the identification of novel alpha(1A )subtype selective 2'-heteroaryl-2-(phenoxymethyl)imidazolines

Novel 2'-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The nature of the 2'-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. alpha(1A) Subtype selective agonists have been identified.     

Chemokine-dependent mechanisms of leukocyte trafficking across a model of the blood-brain barrier

Leukocyte transmigration across the blood-brain barrier (BBB) is a multistep process that can be mediated by chemokines. These low-molecular-weight chemoattractant proteins are secreted by cells within the central nervous system (CNS) in response to injury or on activation. Leukocytes transmigrate toward this chemokine gradient, crossing the BBB and gaining access to the CNS parenchyma. Depending on the chemokine, the nature of the insult, and the type of cell that transmigrates, the BBB integrity may be disrupted, leading to its increased permeability. Both the inflammation resulting from leukocyte transmigration and BBB perturbations contribute to CNS pathology. The mechanisms that mediate leukocyte transmigration and BBB disruption, as well as tissue culture models that are used to study leukocyte trafficking, are the focus of this review.     

Identification of a novel allele of SIR3 defective in the maintenance, but not the establishment, of silencing in Saccharomyces cerevisiae

Using a screen for genes that affect telomere function, we isolated sir3-P898R, an allele of SIR3 that reduces telomeric silencing yet does not affect mating. While sir3-P898R mutations cause no detectable mating defect in quantitative assays, they result in synergistic mating defects in combination with mutations such as sir1 that affect the establishment of silencing. In contrast, sir3-P898R in combination with a cac1 mutation, which affects the maintenance of silencing, does not result in synergistic mating defects. MATa sir3-P898R mutants form shmoo clusters in response to alpha-factor, and sir3-P898R strains are capable of establishing silencing at a previously derepressed HML locus with kinetics like that of wild-type SIR3 strains. These results imply that Sir3-P898Rp is defective in the maintenance, but not the establishment of silencing. In addition, overexpression of a C-terminal fragment of Sir3-P898R results in a dominant nonmating phenotype: HM silencing is completely lost at both HML and HMR. Furthermore, HM silencing is most vulnerable to disruption by the Sir3-P898R C terminus immediately after S-phase, the time when new silent chromatin is assembled onto newly replicated DNA.     

An overview of the structures of protein-DNA complexes

On the basis of a structural analysis of 240 protein-DNA complexes contained in the Protein Data Bank (PDB), we have classified the DNA-binding proteins involved into eight different structural/functional groups, which are further classified into 54 structural families. Here we present this classification and review the functions, structures and binding interactions of these protein-DNA complexes.     

Leakage of a liquid 188Re-filled balloon system during intracoronary brachytherapy. A case report

We are reporting the first case of an accidental radioactive 188Re leakage of a liquid-filled balloon system. Different analytical methods estimated that approximately 4 mCi 188Re were released. The radiation burden was reduced considerably by the combined therapy with perchlorate and forced volume diuresis. Estimated exposures to all organs were very low with 1.8 rad. A total body nuclear scintigraphy demonstrated uniform 188Re distribution, without specific organ concentration.