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Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and [beta]-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear [beta]-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as [beta]-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active [beta]-catenin and dephosphorylated NFAT1 expression. Lung allografts from [beta]-catenin reporter mice demonstrated reduced [beta]-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in [beta]-catenin activation., Introduction Fibrogenesis in the transplanted organ is the predominant cause of allograft failure and death across all solid organs. By 5 years after transplantation, 50% of lung transplant recipients develop [...]

Chronic airway rejection, characterized by lymphocytic bronchitis, epithelial cell damage, and ohliterative bronchiolitis (OB), limits long-term survival after lung transplantation. The transcription factor early growth response gene-1 (Egr-1) induces diverse inflammatory mediators, some involved in OB pathogenesis. An orthotopic mouse tracheal transplant model was used to determine whether Egr-1 promotes development of airway allograft rejection. Significantly higher Egr-1 mRNA levels were seen in allografts (3.2-fold increase vs. isografts, P = 0.012). Allografts revealed thickening of epithelial and subepithelial airway layers (51 [+ or -] 4% luminal encroachment for allografts vs. 20 [+ or -] 3% for isografts, P < 0.0001) marked by significant lymphocytic infiltration. Absence of the Egr-1 gene in donor (but not recipient) tissue resulted in significant reduction in luminal narrowing (34 [+ or -] 4%, P = 0.0001) with corresponding diminution of T cell infiltration. Egr-1 null allografts exhibited a striking reduction in inducible nitric oxide synthase (iNOS) expression. Effector cytokines previously implicated in OB pathogenesis with known Egr- 1 promoter motifs (IL- 1[beta] and JE/monocyte chemoattractant protein-1) were reduced in Egr-1 null allografts. These data suggest a paradigm wherein local induction of Egr-1 in tracheal allografts drives expression of inflammatory mediators responsible for lymphocyte recruitment and tissue destruction characteristic of airway rejection. transplantation; inflammation; lymphocytic bronchiolitis; obliterative bronchiolitis doi:10.1152/ajplung.00285.2006

The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the [...]

Byline: Farid Mokhati, Mourad Badri, Linda Badri, Fathi Hamidane, Sofiane Bouazdia We present, in this paper, a new technique supporting an automatic generation of testing sequences from Agent UML (AUML) diagrams. The considered diagrams are related to agents' interaction protocols. They are formally described using the formal specification language Maude. Starting from the Maude specifications generated automatically from the AUML diagrams, we present a systematic and iterative approach for the construction of testing sequences (sequences of rules) for the verification of the interactions between agents in a Multiagent System (MAS). The approach is organised in two major steps: (1) the generation of Reduced Testing Sequences (RTSs) relative to the individual behaviour of each agent (unit testing of an agent), whose behaviour is described using AUML state charts and (2) the generation of Complete Testing Sequences (CTSs) relative to the collective behaviour of agents (social testing), whose collaborative behaviour is described by an AUML sequence diagram. Furthermore, the proposed approach considers several aspects related to the synchronisation between the agents (inter-agents and external).

Software development is a time and resource consuming process. It is, therefore, important to estimate as soon as possible the effort required to develop software, so that activities can be planned and resources can be optimally allocated. Many software development effort estimation methods have been proposed in the literature. Most of them include software "size" as an important parameter. This study aims at investigating empirically the relationships between use cases attributes and source code size. The research question we wanted to address is to explore the potential of predicting the source code size from use cases attributes only, regardless of technical or environmental factors, which may be difficult to objectively measure. We used in the study four metrics to quantify various use cases attributes and four source code size metrics. In order to investigate the relationships between use cases and source code size metrics, we used three correlation analysis techniques and a clustering technique. The use case metrics have been compared, in terms of relationships with the source code size metrics, to the well-known Use Case Points method. An empirical study, using data collected from five Java open source projects, is reported in the paper. Results provide evidence that a subset of the use case metrics suite is better correlated to the source code size metrics than the Use Case Points values. [ABSTRACT FROM AUTHOR]