Constructing the context through goals and schemata: top-down processes in comprehension and beyond.

My main purpose here is to provide an account of context selection in utterance understanding in terms of the role played by schemata and goals in top-down processing. The general idea is that information is organized hierarchically, with items iteratively organized in chunks-here called "schemata"-at multiple levels, so that the activation of any items spreads to schemata that are the most accessible due to previous experience. The activation of a schema, in turn, activates its other components, so as to predict a likely context for the original item. Since each input activates its own schemata, conflicting schemata compete with (and inhibit) each other, while multiple activations of a schema raise its likelihood to win the competition. There is therefore a double movement-with bottom-up activation of schemata enabling top-down prediction of other contextual components-triggered by multiple sources. Another claim of the paper is that goals are represented by schemata placed at the highest-levels of the executive hierarchy, in accordance with Fuster's model of the brain as a hierarchically organized perception-action cycle. This account can be considered, in part at least, a development of ideas contained in Relevance Theory, though it may imply that some other claims of the theory are in need of revision. Therefore, a secondary purpose of the paper is a contribution to the analysis of that theory.

The effects of being conscious: looking for the right evidence.

Huang & Bargh's (H&B's) general picture might underestimate the role played by conscious self and overestimate the behavioral inconsistencies at the personal level. This follows from how they delimit the goals under consideration: Their theses that goals are not consciously selected and that the conscious self is involved just in post hoc rationalization should also be tested against concrete and long-term goals.

Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells.

Aberrant activation of Notch receptors has been implicated in breast cancer; however, the mechanisms contributing to Notch-dependent transformation remain elusive because Notch displays dichotomous functional activities, promoting both proliferation and growth arrest. We investigated the cellular basis for the heterogeneous responses to Notch pathway activation in 3D cultures of MCF-10A mammary epithelial cells. Expression of a constitutively active Notch-1 intracellular domain (NICD) was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. Interestingly, we found that these heterogeneous phenotypes reflect differences in Notch pathway activation levels; high Notch activity caused down-regulation of multiple matrix-adhesion genes and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. Moreover, microarray analyses implicated NICD-induced p63 down-regulation in loss of matrix adhesion. In addition, a reverse-phase protein array-based analysis and subsequent loss-of-function studies identified STAT3 as a dominant downstream mediator of the NICD-induced outgrowth. These results indicate that the phenotypic responses to Notch are determined by the dose of pathway activation; and this dose affects the balance between growth-stimulative and growth-suppressive effects. This unique feature of Notch signaling provides insights into mechanisms that contribute to the dichotomous effects of Notch during development and tumorigenesis.

Intracellular processing and activation of membrane type 1 matrix metalloprotease depends on its partitioning into lipid domains.

The integral membrane type 1 matrix metalloprotease (MT1-MMP) is a pivotal protease in a number of physiological and pathological processes and confers both non-tumorigenic and tumorigenic cell lines with a specific growth advantage in a three-dimensional matrix. Here we show that, in a melanoma cell line, the majority (80%) of MT1-MMP is sorted to detergent-resistant membrane fractions; however, it is only the detergent-soluble fraction (20%) of MT1-MMP that undergoes intracellular processing to the mature form. Also, this processed MT1-MMP is the sole form responsible for ECM degradation in vitro. Finally, furin-dependent processing of MT1-MMP is shown to occur intracellularly after exit from the Golgi apparatus and prior to its arrival at the plasma membrane. It is thus proposed that the association of MT1-MMP with different membrane subdomains might be crucial in the control of its different activities: for instance in cell migration and invasion and other less defined ones such as MT1-MMP-dependent signaling pathways.