Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alpha(v)beta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease.     

The genome sequence of the filamentous fungus Neurospora crassa

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.     

An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo

The application of RNA interference (RNAi) to mammalian systems has the potential to revolutionize genetics and produce novel therapies. Here we investigate whether RNAi applied to a well-characterized gene can stably suppress gene expression in hematopoietic stem cells and produce detectable phenotypes in mice. Deletion of the Trp53 tumor suppressor gene greatly accelerates Myc-induced lymphomagenesis, resulting in highly disseminated disease. To determine whether RNAi suppression of Trp53 could produce a similar phenotype, we introduced several Trp53 short hairpin RNAs (shRNAs) into hematopoietic stem cells derived from E(mu)-Myc transgenic mice, and monitored tumor onset and overall pathology in lethally irradiated recipients. Different Trp53 shRNAs produced distinct phenotypes in vivo, ranging from benign lymphoid hyperplasias to highly disseminated lymphomas that paralleled Trp53-/- lymphomagenesis in the E(mu)-Myc mouse. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity. Therefore, RNAi can stably suppress gene expression in stem cells and reconstituted organs derived from those cells. In addition, intrinsic differences between individual shRNA expression vectors targeting the same gene can be used to create an 'epi-allelic series' for dissecting gene function in vivo.     

Power-Based Arbitrary Decisional Actions in the Resolution of MIS Project Issues: A Project Manager's Action Research Perspective

As a management information systems (MIS) project manager and an action researcher, the author examined, over time, the influence on information system development (ISD) of the informal sociopolitical organizational actions. The paper reports two cases of action research findings concerning the effect on ISD project implementation processes of power-based arbitrary decisional actions in bureaucratic environments. The research focused on the relationship of such unilateral actions to the interconnected subprocesses of deliberate and conscious attempts by the ISD project members to define and resolve system implementation issues. A suggested conceptual framework for the issue-resolution processes (IRP's) and obstacle-coping processes (OCP's) is based on the author's IRP/OCP-related behavioral constructs and theoretical models dealing with soft-systems issues, especially appreciative system theory and soft-systems methodology, and innovative flexible, "complementarist" (Sinn, 1998) or pluralist problem-solving approaches.     

Inter-simple sequence repeat (ISSR) variation in three populations of Gaura neomexicana ssp. coloradensis (Onagraceae), F.E. Warren Air Force Base, Cheyenne, Wyoming

We investigated genetic variation within and between 3 populations of Gaura neomexicana ssp. coloradensis , a federally listed threatened species, using inter-simple sequence repeats. The data matrix included 24 individuals scored for 88 bands, with 3.4% missing data. Cluster analysis showed that members of the 3 populations are very similar and are intermixed in the phenogram. Principal coordinate analysis indicated that members of the Crow Creek population are different from the Diamond Creek and ""unnamed drainage"" populations. This could be the result of historic differences, current changes in vegetation at the Crow Creek site, or an artifact of limited sampling. In any case, for management purposes it is best to preserve the dwindling population at Crow Creek as well as the thriving populations at the other 2 sites.     

Evaluation practice and the tricky issue of coercive contexts

Recently, the study of evaluation theory and practice has been elevated to a position of prominence. However, while evaluation theory is burgeoning, failure to consider situations of coercion and oppression renders evaluation practice fundamentally deficient. In this paper the search for appropriate methods of evaluation for use in coercive contexts is initiated. Based on Flood and Jackson's (1991) recommendation for the use of Ulrich's Critical System Heuristics (1983) in coercive contexts, the principles of this methodology are used to guide the search. Following the alignment of Critical System Heuristics with Stake's Responsive Evaluation (1980), the potential contribution of critical evaluation methodologies to the general field of critical management studies is assessed.     

The infectiousness of pompous prose.

For centuries, scientists have been bombarded with pleas for plain language. Why have these pleas had no effect, when the problem of unreadable prose could be solved at a stroke?