Connective tissue growth factor (CTGF) is a matricellular protein that mediates cell-matrix interaction through various subtypes of integrin receptors. This study investigated the role of CTGF and integrin αvβ6 in hepatic progenitor/oval cell activation, which often occurs in the form of ductular reactions (DRs) when hepatocyte proliferation is inhibited during severe liver injury. CTGF and integrin αvβ6 proteins were highly expressed in DRs of human cirrhotic livers and cholangiocarcinoma. Confocal microscopy analysis of livers from Ctgf promoter driven GFP reporter mice suggested that oval cells and cholangiocytes were the main sources of CTGF and integrin αvβ6 during liver injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Deletion of exon 4 of the Ctgf gene using tamoxifen inducible Cre-loxP system down-regulated integrin αvβ6 in DDC damaged livers of knockout mice. Ctgf deficiency or inhibition of integrin αvβ6 by administrating the neutralizing antibody 6.3G9 (10 mg/kg body weight) caused low levels of EpCAM and CK19 mRNAs. Also, there were smaller oval cell areas, fewer proliferating ductular epithelial cells, and lower cholestasis serum markers within two weeks after DDC treatment. Associated fibrosis was attenuated as indicated by reduced expression of fibrosis-related genes, smaller areas of α smooth muscle actin staining and low collagen production based on hydroxyproline content and the Sirius red staining. Finally, integrin αvβ6 could bind to CTGF mediating oval cell adhesion to CTGF and fibronection substrata and promoting transforming growth factor (TGF)-β1 activation in vitro. Conclusions: CTGF and integrin αvβ6 regulate oval cell activation and fibrosis, probably through interacting with their common matrix and signal partners, fibronectin and TGF-β1. CTGF and integrin αvβ6 are potential therapeutic targets to control DRs and fibrosis in related liver disease.

Active learning and research-oriented activities have been increasingly used in smaller, specialized science courses. Application of this type of scientific teaching to large enrollment introductory courses has been, however, a major challenge. The general microbiology lecture/ laboratory course described has been designed to incorporate published active-learning methods. Three major case studies are used as platforms for active learning. Themes from case studies are integrated into lectures and laboratory experiments, and in class and online discussions and assignments. Students are stimulated to apply facts to problem-solving and to learn research skills such as data analysis, writing, and working in teams. This course is feasible only because of its organizational framework that makes use of teaching teams (made up of faculty, graduate assistants, and undergraduate assistants) and Web-based technology. Technology is a mode of communication, but also a system of course management. The relevance of this model to other biology courses led to assessment and evaluation, including an analysis of student responses to the new course, class performance, a university course evaluation, and retention of course learning. The results are indicative of an increase in student engagement in research-oriented activities and an appreciation of real-world context by students.Keywords: active learning, case studies, introductory biology, undergraduate students, technology INTRODUCTIONMany reports in the science education literature have shown that our traditional lecture offerings and accompanying ''cookbook'' labs are missing the educational mark. The concern reverberating in the science education community is that we need to transform our classes from instructor-led courses to dynamic student-centered learning arenas that engage our students in research-oriented learning (Wood, 2003; National Research Council [NRC], 2003). This has led to a call to arms in research universities. Despite the farreaching concern and the availability of proven methods for incorporating active learning into our courses (Handelsman et al., 2004), many of us teaching large lecture introductory classes have been leery of making a transition. At first consideration it seems straightforward to add a few new teaching strategies to a course. But when faced with 200 students and more in a lecture hall, even distributing a handout requires layers of organization (must plan for the time in the class period for distribution, for the method of distribution to ensure that all students receive the handout and to ensure that students do not take extra copies, and for the method to reach absent students). Upon reflection, even enthusiastic and energetic teachers quickly realize that converting a large-enrollment, lecture-based class to a course with an active-learning foundation will require time and organization. For faculty at a research university with already significant demands besides teaching, the choice to develop a framework to support active learning ca...

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SUMMARYIntegrin aEb7 is expressed almost exclusively by mucosal T cells and mucosal dendritic antigenpresenting cells (APCs) and is thought to be induced locally by transforming growth factor-b (TGF-b). In mice, mRNA for the aE subunit was found to be abundant in mucosal T cells but absent from other tissues. Exposure of a T-cell line to TGF-b strongly up-regulated aE mRNA levels within 30 min, and nuclear run-on experiments established that regulation occurred at the level of transcription. The organization of the human aE gene and a very closely linked novel gene, ELG, was determined. The aE promoter was tested in T cells and ®broblasts and functioned equally well in both cell types and did not confer TGF-b responsiveness. Regions of the promoter providing enhancer activity and phorbol 12-myristate 13-acetate (PMA) responsiveness were identi®ed by deletion studies. DNAse 1 hypersensitivity analysis of 36 kb of the aE gene revealed one hypersensitive site, found only in aE + cells, located near the transcription start points. These results show that, unlike the situation with other integrins, lineage speci®city and cytokine responsiveness of aE transcription are not conferred by the proximal promoter. Speci®city may depend on distant control elements that have not yet been identi®ed.

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