Unconventional myosin proteins of the MyTH-FERM superclass are involved in intrafilopodial trafficking, are thought to be mediators of membrane-cytoskeleton interactions, and are linked to several forms of deafness in mammals. Here we show that the Drosophila myosin XV homolog, Sisyphus, is expressed at high levels in leading edge cells and their cellular protrusions during the morphogenetic process of dorsal closure. Sisyphus is required for the correct alignment of cells on opposing sides of the fusing epithelial sheets, as well as for adhesion of the cells during the final zippering/fusion phase. We have identified several putative Sisyphus cargos, including DE-cadherin (also known as Shotgun) and the microtubule-linked proteins Katanin-60, EB1, Milton and aPKC. These cargos bind to the Sisyphus FERM domain, and their binding is in some cases mutually exclusive. Our data suggest a mechanism for Sisyphus in which it maintains a balance between actin and microtubule cytoskeleton components, thereby contributing to cytoskeletal cross-talk necessary for regulating filopodial dynamics during dorsal closure.

Objective-Social norms have been associated with a wide range of health behaviors. In this study, we examined whether the social norms of HIV risk behaviors are clustered within social networks and whether the norms of network members are linked to the risk behaviors of their social network members.Design-Data were collected from the baseline assessment of 354 networks with 933 participants in a network oriented HIV prevention intervention targeting injection drug users (IDUs) in the Philadelphia, US and Chiang Mai, Thailand.Main Outcome Measures-Four descriptive HIV risk norms of sharing needles, cookers, and cotton and front or back-loading among friends who inject were assessed.Results-Three of four injection risk norms (sharing needle, cookers, and cotton) were found to be significantly clustered. In Philadelphia, one network member's (the index participant) norms of sharing needles and front or back-loading were found to be significantly associated with the network members' risk behaviors, and the norm of sharing cotton was marginally associated. Conclusion-The results of this study suggest that among injection drug users, social norms are clustered within networks; social networks are a meaningful level of analyses for understanding how social norms lead to risk behaviors, providing important data for intervening to reduce injection related HIV risks. In this study, we examined how social norms of HIV risk behaviors are structured within social networks and how these norms may be linked to subsequent risk behavior. A critical issue in altering health behaviors is how individual-level behavior change can be leveraged into group or community level change. How can a minority of individuals who have adopted a new set of health behaviors lead to acceptance and adoption of these behaviors within the larger community (Prislin & Christensen, 2005)? One conceptual approach to community level change is through social diffusion, wherein prominent individuals within a group, known as early adopters, first embrace a new behavior (Rogers, 2003). It has been hypothesized that successful social diffusion early adopters lead others to change their behavior. In this manner, the new behavior is diffused through the community. Social diffusion has been used to evaluate changes in antibiotic prescribing practices, uptake of medical technology, and the spread of fads and new commercial products (Jacobsen & Guastello, 2007;Hashimoto et al., 2006;Van den Bulte & Lilien, 2001). KeywordsInvestigators have utilized the process of social diffusion information for planned behavioral interventions. Opinion leader models of health behavior change have utilized influential individuals to diffuse changes in health behaviors. In the field of HIV prevention, community opinion leaders' models of behavior change have been successful in reducing risk behaviors in many but not all studies (Elford, Bolding, & Sherr, 2004;Kelly et al., 1991;Sikkema et al, 2005). Although several opinion leader interventions have been successful in alterin...

Integration of patterning cues via transcriptional networks to coordinate gene expression is critical during morphogenesis and misregulated in cancer. Using DNA adenine methyltransferase (Dam)ID chromatin profiling, we identified a protein-protein interaction between the Drosophila Myc oncogene and the Groucho corepressor that regulates a subset of direct dMyc targets. Most of these shared targets affect fate or mitosis particularly during neurogenesis, suggesting the dMyc-Groucho complex may coordinate fate acquisition with mitotic capacity during development. We find an antagonistic relationship between dMyc and Groucho that mimics the antagonistic interactions found for EGF and Notch signaling: dMyc is required to specify neuronal fate and enhance neuroblast mitosis, whereas Groucho is required to maintain epithelial fate and inhibit mitosis. Our results suggest that the dMyc-Groucho complex defines a previously undescribed mechanism of Myc function and may serve as the transcriptional unit that integrates EGF and Notch inputs to regulate early neuronal development.neurogenesis ͉ Drosophila ͉ stem cell ͉ cell fate ͉ mitosis

ELF5, an Ets family transcription factor found exclusively in epithelial cells, is expressed in the distal lung epithelium during embryogenesis, then becomes restricted to proximal airways at the end of gestation and postnatally. To test the hypothesis that ELF5 represses distal epithelial differentiation, we generated a transgenic mouse model in which a doxycycline inducible HA-tagged mouse Elf5 transgene was placed under the control of the lung epithelium-specific human SFTPC promoter. We found that expressing high levels of ELF5 during early lung development disrupted branching morphogenesis and produced a dilated epithelium. The effects of ELF5 on morphogenesis were stage-dependent, since inducing the transgene on E16.5 had no effect on branching. ELF5 reduced expression of the distal lung epithelial differentiation markers Erm, Napsa and Sftpc, and type II cell ultrastructural differentiation was immature. ELF5 overexpression did not induce the proximal airway epithelial markers Ccsp and Foxj1, but did induce expression of p63, a marker of basal cells in the trachea and esophagus. High ELF5 levels also induced the expression of genes found in other endodermal epithelia but not normally associated with the lung. These results suggest that precise levels of ELF5 regulate the specification and differentiation of epithelial cells in the lung.

Fibroblast growth factor (FGF) signaling has been shown to be essential for many aspects of normal lung development. To determine epithelial targets of FGF signaling, we cultured embryonic day (E) 11.5 mouse lungs for 24 hr in the presence or absence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis of treated and control epithelia identified several genes regulated by FGF signaling, including Elf5, a member of the Epithelial-specific Ets family of transcription factors. SU5402 reduced Elf5 expression in mesenchyme-free cultures of E12.5 epithelium, demonstrating that the inhibition was direct. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development. We found that expression of Elf5 was induced by FGF7 and FGF10, ligands that primarily bind FGFR2b. To further define the pathways by which FGFs activate Elf5 expression, we cultured E11.5 lung tips in the presence of compounds to inhibit FGF receptors (SU5402), PI3-Kinase/Akt-mediated signaling (LY294002), and MAP Kinase/Erk-mediated signaling (U0126). We found that SU5402 and LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. LY294002 also reduced Elf5 expression in cultures of purified epithelium. Finally, pAkt was coexpressed with Elf5 in the proximal epithelial airways of E17.5 lungs. These results demonstrate that Elf5 is an FGF-sensitive transcription factor in the lung with a dynamic pattern of expression and that FGF regulation of Elf5 by means of FGFR2b occurs through the PI3-Kinase/Akt pathway.

SUMMARYPancreatic -cells arise from Ngn3 + endocrine progenitors within the trunk epithelium of the embryonic pancreas. The emergence of endocrine cells requires E-cadherin downregulation, but the crucial steps that elicit such are not clear, yet probably important for ultimately being able to efficiently generate -cells de novo from stem cells. Grg3 (groucho-related gene 3, also known as Tle3), encodes a member of the Groucho/TLE family of co-repressors and its function in various cell contexts is mediated by recruitment to target genes by different transcription factors. Grg proteins broadly regulate the progression of progenitor cells to differentiated cell types, but specific developmental mechanisms have not been clear. We find that Grg3 is expressed in most -cells and a subset of other endocrine cell types in the pancreas. Grg3 is highly expressed in Ngn3 + endocrine progenitor descendants just after transient Ngn3 expression. Grg3-null embryos die at E14.5, which is associated with placental defects, so we explanted E12.5 pancreata to allow endocrine differentiation to occur in culture. Grg3 knockout explants displayed a drastic decrease in the differentiation of all endocrine cell types owing to defects in the delamination of early endocrine progenitors from the trunk epithelium. We find that Grg3 normally suppresses E-cadherin gene expression, thereby allowing delamination of endocrine cells from the trunk epithelium and revealing how this transcriptional co-repressor modulates this crucial step of -cell development.

Employment has been identified as a major goal of drug abuse treatment yet few rigorous tests of employment-related interventions have been conducted. A10-session, manual-guided vocational cognitive problem-solving intervention was evaluated at five methadone treatment sites in an effort to reduce the high unemployment rate among methadone clients. The group intervention focused on helping participants explore the value they place on work, identifying social and psychological barriers to work, developing action strategies to overcome those barriers, setting realistic expectations of work, and taking action. At six months post-intervention, the experimental group (N = 67) demonstrated a significant increase in employment rate (13.4% to 26.9%); no significant change occurred for controls (N = 63). At 12 months post-intervention, however, overall employment gains declined in the experimental group, suggesting the need for additional intervention in order to maintain employment gains.

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