Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors.

The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration.

Understanding liver regeneration to bring new insights to the mechanisms driving cholangiocarcinoma.

Cancer frequently arises in epithelial tissues subjected to repeated cycles of injury and repair. Improving our understanding of tissue regeneration is, therefore, likely to reveal novel processes with inherent potential for aberration that can lead to carcinoma. These highly conserved regenerative mechanisms are increasingly understood and in the liver are associated with special characteristics that underlie the organ's legendary capacity for restoration of size and function following even severe or chronic injury. The nature of the injury can determine the cellular source of epithelial regeneration and the signalling mechanisms brought to play. These observations are shaping how we understand and experimentally investigate primary liver cancer, in particular cholangiocarcinoma; a highly invasive malignancy of the bile ducts, resistant to chemotherapy and whose pathogenesis has hitherto been poorly understood. Interestingly, signals that drive liver development become activated in the formation of cholangiocarcinoma, such as Notch and Wnt and may be potential future therapeutic targets. In this review, we summarise the work which has led to the current understanding of the cellular source of cholangiocarcinoma, how the tumour recruits, sustains and is educated by its supporting stromal environment, and the tumour-derived signals that drive the progression and invasion of the cancer. With few current treatments of any true efficacy, advances that will improve our understanding of the mechanisms driving this aggressive malignancy are welcome and may help drive therapeutic developments.

Integrin signalling regulates the expansion of neuroepithelial progenitors and neurogenesis via Wnt7a and Decorin.

Development of the cerebral cortex requires regulation of proliferation and differentiation of neural stem cells and a diverse range of progenitors. Recent work suggests a role for extracellular matrix (ECM) and the major family of ECM receptors, the integrins. Here we show that enhancing integrin beta-1 signalling, by expressing a constitutively active integrin beta-1 (CA*ß1) in the embryonic chick mesencephalon, enhances neurogenesis and increases the number of mitotic cells dividing away from the ventricular surface, analogous to sub-apical progenitors in mouse. Only non-integrin-expressing neighbouring cells (lacking CA*ß1) contributed to the increased neurogenesis. Transcriptome analysis reveals upregulation of Wnt7a within the CA*ß1 cells and upregulation of the ECM protein Decorin in the neighbouring non-expressing cells. Experiments using inhibitors in explant models and genetic knock-downs in vivo reveal an integrin-Wnt7a-Decorin pathway that promotes proliferation and differentiation of neuroepithelial cells, and identify Decorin as a novel neurogenic factor in the central nervous system.

Effects of hierarchical organization on children's judgments of distance and direction.

The impact of the hierarchical organization of a space on judgments of direction and distance was assessed in two studies using two-dimensional models analogous to those used by A. Stevens and P. Coupe (1978, Cognitive Psychology, 10, 422-437). In each study the models contained two stars and were divided into two parts by a curved boundary line. In the Homogeneous condition the stars were located in the same subsection. In the Congruent condition the leftmost star was in the left subsection and the rightmost star was in the right subsection. In the Incongruent condition the rightmost star was in the left subsection and the leftmost star was in the right subsection. In Experiment 1 first graders, third graders, and college students were required to remember the location of the stars. Results indicated that the first and third graders tended to use the relationship between the subsections as a clue to the relationship between the sites within them, thus extending the results of Stevens and Coupe (1978) to children. In Experiment 2 preschoolers, first, and third graders were asked to judge with the materials directly in front of them, which of the two stars was closer to a site located in one of the subsections. Results indicated that the Incongruent condition led to errors among the preschoolers and first graders but not the third graders, thus indicating that these groups tended to judge as closer the site within the same subsection even though it was really farther away. The results of both studies are discussed as indicative of a tendency among young children to impose organization on information encoded in memory and in relation to increases in metric accuracy, decentration, and efficient scanning which enable them to more accurately evaluate when such organization is and is not appropriate. Implications for behavior in large-scale environments are also discussed, with particular reference to the effect of barriers on perceptions of distance and direction.

Attention and reaction times to signals of uncertain modality.

Visual, auditory, and tactile reaction time (RT) signals were used in an a-reaction task. The main independent variable was the predictability of signal modality, which was varied by cuing the relevant modality or modalities before each trial. The response requirement was nondiscriminative with respect to modality. Three experiments showed that (a) RT's were longer when signal modality was uncertain, the more so with three possible modalities than with two; (b) this effect of uncertainty was approximately the same whether varied within subjects or between subjects; and (C) the effect of uncertainty was somewhat smaller on tactile RTs than on visual or auditory RTs. Experiment 4 examined change in this uncertainty effect with practice. The uncertainty effect declined over 11 daily sessions to the point of virtual absence from auditory and tactile RTs but was restored or increase will respect to all three signals following one session of discrimination RTs ("respond if visual, refrain if auditory or tactile"). The results are interpreted as showing that attention can be allocated to sensory modalities and that the implied selective process is concerned with modality "identification," though not in a way consistent with a channel-switching model thereof.