Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer.

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

Pluralization instruction in comprehension and production.

Four retarded children who did not comprehend or produce plurals were taught to pluralize by adding /s/ to words like hat/hats, cup/cups. Half of the children were first taught the rule in comprehension (pointing to single and multiple arrays of objects) and then in production (labeling the same arrays). The remaining two children were taught first to produce and then to comprehend plurals. In each sequence, one child demonstrated facilitation from the first taught modality to the second, as evidenced by rapid and efficient learning of the rule in the second modality. The sequence in which comprehension and production were taught did not affect the facilitation, however. The children were taught in two environments, an experimental room and an ordinary classroom.