Mesenchymal–epithelial interactions during digestive tract development and epithelial stem cell regeneration

The gastrointestinal tract develops from a simple and uniform tube into a complex organ with specific differentiation patterns along the anterior–posterior and dorso-ventral axes of asymmetry. It is derived from all three germ layers and their cross-talk is important for the regulated development of fetal and adult gastrointestinal structures and organs. Signals from the adjacent mesoderm are essential for the morphogenesis of the overlying epithelium. These mesenchymal–epithelial interactions govern the development and regionalization of the different gastrointestinal epithelia and involve most of the key morphogens and signaling pathways, such as the Hedgehog, BMPs, Notch, WNT, HOX, SOX and FOXF cascades. Moreover, the mechanisms underlying mesenchyme differentiation into smooth muscle cells influence the regionalization of the gastrointestinal epithelium through interactions with the enteric nervous system. In the neonatal and adult gastrointestinal tract, mesenchymal–epithelial interactions are essential for the maintenance of the epithelial regionalization and digestive epithelial homeostasis. Disruption of these interactions is also associated with bowel dysfunction potentially leading to epithelial tumor development. In this review, we will discuss various aspects of the mesenchymal–epithelial interactions observed during digestive epithelium development and differentiation and also during epithelial stem cell regeneration.     

Investigation of an energy nonadditivity for nonextensive systems

We investigate the energy nonadditivity relationship E(AαB) = E(A) + E(B) + αE(A)E(B) which is often considered in the development of the statistical physics of nonextensive systems. It was recently found that α in this equation was not constant for a given system in a given situation and could not characterize nonextensivity for that system. In this work, we select several typical nonextensive systems and compute the behavior of α when a system changes its size or is divided into subsystems in different fashions. Three kinds of interactions are considered. It is found by a thought experiment that α depends on the system size and the interaction as expected and on the way we divide the system. However, one of the major results of this work is that, for given system, α has a minimum with respect to division position. Around this position, there is a zone in which α is more or less constant, a situation where the sizes of the subsystems are comparable. The width of this zone depends on the interaction and on the system size. We conclude that if α is considered approximately constant in this zone, the two mathematical difficulties raised in previous studies are solved, meaning that the nonadditive relationship can characterize the nonadditivity of the system as an approximation. In all the cases, α tends to zero in the thermodynamic limit (N→∞) as expected.     

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.     

Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity

Cell polarity is a fundamental property of all cells. In higher eukaryotes, the small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division and directed cell migration. However, little is known about what lies downstream of this complex. Here we show, through the use of primary rat astrocytes in a cell migration assay, that Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome and to control the direction of cell protrusion. Cdc42-dependent phosphorylation of GSK-3beta occurs specifically at the leading edge of migrating cells, and induces the interaction of adenomatous polyposis coli (Apc) protein with the plus ends of microtubules. The association of Apc with microtubules is essential for cell polarization. We conclude that Cdc42 regulates cell polarity through the spatial regulation of GSK-3beta and Apc. This role for Apc may contribute to its tumour-suppressor activity.     

Multilevel Innovation in Remote Networked Schools

Small remote rural schools in Quebec face an ongoing challenge to provide similar quality educational services than bigger schools. Since 2002, the Remote Network Schools (RNS) initiative afforded schools the opportunity to reinvent their practice by using online tools to experience collaborative learning activities with other remote schools. Teachers and students experienced quality learning and demonstrated agency by implementing the RNS in their context. Measures include: diversity of learning activities, quality of online classroom interactions, changes in teacher beliefs, and shifts in teacher and student roles. Our results show that it is a viable operating method for such schools and that other schools could contemplate implementing such innovative practices.     

Massive glycosaminoglycan-dependent entry of Trp-containing cell-penetrating peptides induced by exogenous sphingomyelinase or cholesterol depletion

Among non-invasive cell delivery strategies, cell-penetrating peptide (CPP) vectors represent interesting new tools. To get fundamental knowledge about the still debated internalisation mechanisms of these peptides, we modified the membrane content of cells, typically by hydrolysis of sphingomyelin or depletion of cholesterol from the membrane outer leaflet. We quantified and visualised the effect of these viable cell surface treatments on the internalisation efficiency of different CPPs, among which the most studied Tat, R₉, penetratin and analogues, that all carry the N-terminal biotin-Gly₄ tag cargo. Under these cell membrane treatments, only penetratin and R₆W₃ underwent a massive glycosaminoglycan (GAG)-dependent entry in cells. Internalisation of the other peptides was only slightly increased, similarly in the absence or the presence of GAGs for R₉, and only in the presence of GAGs for Tat and R₆L₃. Ceramide formation (or cholesterol depletion) is known to lead to the reorganisation of membrane lipid domains into larger platforms, which can serve as a trap and cluster receptors. These results show that GAG clustering, enhanced by formation of ceramide, is efficiently exploited by penetratin and R₆W₃, which contains Trp residues in their sequence but not Tat, R₉ and R₆L₃. Hence, these data shed new lights on the differences in the internalisation mechanism and pathway of these peptides that are widely used in delivery of cargo molecules.     

Recommendations of the 2006 Human Variome Project meeting

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.     

Systemic Evaluation Methodology: The Emergence of Social Learning From Environmental ICT Prototypes

This paper investigates why and how systems approaches can help in evaluating the design of new Information and Communication Technologies (ICTs) as social learning platforms. It focuses on the prototypes created by the research project Virtualis, whose objective is to promote social learning on environmental concepts and practices amongst a variety of stakeholders. The paper presents the principles of systems thinking and practice that did help in formulating such evaluation processes. It illustrates how both a peer systemic evaluation process (within the research team) and a participatory evaluation process (involving potential future users of the ICTs) were carried out.     

Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties

The cellular prion protein PrP(C)/CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrP(C) displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrP(C) displays important similarities with the HIV-1 nucleocapsid protein and found that PrP(C) expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrP(C) mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrP(C) binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrP(C) colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrP(C) in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.