Elucidating the interactions between the adhesive and transcriptioanl functions of beta-catenin in normal and cancerous cells

Wnt signalling is involved in a wide range of physiological and pathological processes. The presence of an extracellular Wnt stimulus induces cytoplasmic stabilisation and nuclear translocation of beta-catenin, a protein that also plays an essential role in cadherin-mediated adhesion. Two main hypotheses have been proposed concerning the balance between beta-catenin's adhesive and transcriptional functions: either beta-catenin's fate is determined by competition between its binding partners, or Wnt induces folding of beta-catenin into a conformation allocated preferentially to transcription. The experimental data supporting each hypotheses remain inconclusive. In this paper we present a new mathematical model of the Wnt pathway that incorporates beta-catenin's dual function. We use this model to carry out a series of in silico experiments and compare the behaviour of systems governed by each hypothesis. Our analytical results and model simulations provide further insight into the current understanding of Wnt signalling and, in particular, reveal differences in the response of the two modes of interaction between adhesion and signalling in certain in silico settings. We also exploit our model to investigate the impact of the mutations most commonly observed in human colorectal cancer. Simulations show that the amount of functional APC required to maintain a normal phenotype increases with increasing strength of the Wnt signal, a result which illustrates that the environment can substantially influence both tumour initiation and phenotype.

Young people with learning disabilities who sexually harm others: the role of criminal justice within a multi-agency response

This paper outlines the key findings from a recent study of statutory service responses to young people with learning disabilities who show sexually inappropriate or abusive behaviours, with a particular focus on the involvement of criminal justice agencies. The study found that although inappropriate sexual behaviours were commonplace in special schools, and that serious acts of abuse including rape had sometimes occurred, education, welfare and criminal justice agencies struggled to work together effectively. In particular, staff often had difficulty in determining the point at which a sexually inappropriate behaviour warranted intervention. This problem was frequently compounded by a lack of appropriate therapeutic services. In many cases this meant that no intervention was made until the young person committed a sexual offence and the victim reported this to the police. As a consequence, young people with learning disabilities are being registered as sex offenders. The paper concludes by addressing some of the policy and practice implications of the study’s findings, particularly those which relate to criminal justice.