mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex.

In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-α as well as IL-1ß induced the phosphorylation of TSC2, especially on S939 via the PI3-K/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.

The contribution of William James to the origins of "scientific" psychology.

This paper illustrates the specific nature of the contribution made by the psychology of William James to the construction of modern scientific psychology. Universally recognized as the father of American scientific psychology, William James still remains a much-debated scientist, mainly for two reasons. First, he was interested in subjects that were often very far from the narrow and traditional approaches taken by the greater part of his contemporary colleagues. Secondly, in order to enlighten psychological issues, he continued to adopt multidisciplinary contributions, rather than selecting only those that stemmed from experimental and specifically laboratory contexts. James has been recently inserted in the more complex international consortium of psychologists, psychiatrists, physicians, psychotherapists, and philosophers that has been called "the French-Swiss-English-and-American psychotherapeutic alliance." This does in reality seem a more appropriate framework for understanding the specificity of James's psychology. In order to illustrate the peculiar Jamesian way of thinking about psychological issues, this paper undertakes an examination of his classical concept of the "stream of thought." Here, in fact, many different contributions converge in defining and outlining "the primary fact of consciousness"--personal, subjective, and introspective observation; philosophical arguments; "mental experiments," and psychopathological experiences; but, most of all, neurological data derived specifically from brain physiology. This last contribution has been too often underestimated, as has also the background of James's training in the development of experimental psychology, neurology, and physiology at Harvard before 1890. The paper concludes with the assertion that James represents the prototype of a new way of defining the scientific quality of modern psychology, far from the narrow definition given by the laboratory experimentalists fresh from the German universities at the end of the nineteenth century.