Functional inactivation of Cdk9 through oligomerization chain reaction.

The oligomerization chain reaction (OCR) strategy is a recently described technique for inactivation of target proteins that function as homoassociate complexes. This novel strategy is based on the fusion of self-associating coiled-coil (CC) domain of the nuclear factor promyelocytic leukemia (PML) to target proteins. Here, we present the successful application of the OCR strategy for inactivation of the heterodimeric Cdk9/cyclin T1 complex. Cyclin T1/Cdk9 (P-TEFb) complex is a positive regulator of gene transcription, whose function is underlined by the ability to phosphorylate the carboxyl-terminal domain (CTD) of the RNA polymerase II conferring productive transcript elongation. Fusion of the CC domain to Cdk9 leads to the formation of high molecular complexes to which the endogenous cyclin T1 is recruited. The CC-Cdk9 chimera effectively inhibits HIV-1 Tat activation, whose transcription activity is exquisitely dependent upon cyclin T1/Cdk9 function. Furthermore, expression of CC-Cdk9 protein inhibits cell proliferation, as shown by colony-formation assay. Collectively, our findings add further support to the OCR strategy for functional inactivation of hetero-associated factors such as the Cdk9/cyclin T1 complex, and highlight a putative function of Cdk9 in cell growth control.

From models to rules: mechanization of reasoning as a way to cope with cognitive overloading in combinatorial problems.

It is hypothesized that the transition from unfamiliar problems to familiar, well-learned problems coincides with the transition from a model-based style of reasoning to a rule-based style of reasoning; model-based style of reasoning helps understanding the problem structure, but can overload working memory when the number of models required increases; rule-based style of reasoning avoids cognitive overloading, at the cost of making individuals liable to mechanization errors. In Experiment 1, the number of models required to respond to a verification task affected response latencies with unfamiliar problems, but not with familiar problems, supporting the initial hypothesis. In Experiment 2, participants were prone to mechanization errors when confronted with slightly modified problems in the late stages of the experiment, supporting the hypothesis that they had developed a reasoning rule in the early stages and were blindly applying it. The findings suggest that model-based reasoning and rule-based reasoning serve different purposes and have different costs and benefits, are both available to human reasoners, and familiarization with a problem may induce the transition from the former to the latter. The findings also suggest that mechanization of reasoning may be the first step along a gradient of decreasing cognitive load, whose end-point is automatization, as discussed in theories of automatization of information processing.

Facilitation and inhibition caused by the orienting of attention in propositional reasoning tasks.

In an attempt to study the orienting of attention in reasoning, we developed a set of propositional reasoning tasks structurally similar to Posner's (1980) spatial cueing paradigm, widely used to study the orienting of attention in perceptual tasks. We cued the representation in working memory of a reasoning premise, observing whether inferences drawn using that premise or a different, uncued one were facilitated, hindered, or unaffected. The results of Experiments 1a, 1b, 1c, and 1d, using semantically (1a-1c) or statistically (1d) informative cues, showed a robust, long-lasting facilitation for drawing inferences from the cued rule. In Experiment 2, using uninformative cues, inferences from the cued rule were facilitated with a short stimulus onset asynchrony (SOA), whereas they were delayed when the SOA was longer, an effect that is similar to the "inhibition of return" (IOR) in perceptual tasks. Experiment 3 used uninformative cues, three different SOAs, and inferential rules with disjunctive antecedents, replicating the IOR-like effect with the long SOAs and, at the short SOA, finding evidence of a gradient-like behaviour of the facilitation effect. Our findings show qualitative similarities to some effects typically observed in the orienting of visual attention, although the tasks did not involve spatial orienting.