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At least 685 records · Page 38Linked to original sources
PubMed2006

The combi-targeting concept: evidence for the formation of a novel inhibitor in vivo.

With the purpose of developing drugs that can block multiple targets in tumor cells, molecules termed combi-molecules or TZ-I have been designed to be hydrolyzed in vitro to TZ+I, where TZ is a DNA-damaging species and I is an inhibitor of the epidermal growth factor receptor (EGFR). Using HPLC and liquid chromatography-mass spectrometry (LC-MS), we investigated the mechanism of in vivo degradation of a prototype of one such combi-molecule, ZRBA1, which when administered i.p. rapidly degraded into FD105 (Cmax=50 micromol/l, after 30 min), a 6-aminoquinazoline that was N-acetylated to give FD105Ac (IAc) (Cmax=18 micromol/l, after 4 h). A similar rate of acetylation was observed when independently synthesized FD105 was administered i.p. More importantly, the EGFR binding affinity of IAc was 3-fold greater than that of I, indicating that the latter is converted in vivo into an even more potent EGFR inhibitor. The results in toto suggest that while in vitro TZ-I is only hydrolyzed to I+TZ, further acetylation of I in vivo leads to a third component--a highly potent EGFR inhibitor with a delayed Cmax.

Acetylation↗
PubMed1999

Neurobiological bases of behavioral development in the second year.

We discuss selected psychological competences that develop and become noticeable between one and two years of age and are temporally correlated to structural, biochemical and physiological changes in the brain. The psychological competences are: Language development, a sense of "right" and "wrong", self-awareness, and the ability to make inferences. The accompanying changes in the brain involve the prefrontal cortex, language-related cortical areas, hippocampus, cerebellum, basal ganglia and an increase in the connectivity of the network. Of special interest are the maturational changes in layers III-IV of the prefrontal cortex. Layer III is the origin and target of callosal and commissural axons linking the two hemispheres and the target of associational axons linking ipsilateral areas within each hemisphere. Layer IV, the target for axons from the mediodorsal nucleus of the thalamus, conveys information from other associational cortices, cerebellum, basal ganglia, and the reticular and limbic systems. In the second year, intensive dendritic growth and synaptogenesis in these layers increase the linking of these two layers and form a neural basis for a more efficient convergence and integration of information from the two hemispheres, which are functionally asymmetric. It is our hypothesis that these changes, together with the maturational changes in the cortico-subcortical network, are a basis for the observed emergence of the psychological competences. We are aware that temporal correlations cannot prove firm causal relationships. However, knowledge of these correlations is useful in generating specific hypotheses that can be tested directly.

Axons↗
PubMed1992

Choosing specifiers: an evaluation of the basic tasks model of graphical perception.

Effect sizes obtained from 39 experiments were used to evaluate the predictions of the basic tasks model of graphical efficacy. This model predicts that performance will be attenuated with graphical displays as a function of the particular specifier, or visual dimension, used to code data values. In this review the basic tasks model predicted performance more accurately than did Tufte's data-ink principle. In addition, variability in effect sizes across studies revealed that the model was more successful at predicting performance in local (focusing) tasks than in global information synthesis tasks. Furthermore, the model was better at predicting performance in tasks requiring the use of physically present rather than remembered graphs. Further differences in effect sizes resulted from variability in the exact specifiers used in experimental graphs. Minimal differences were obtained among graphs that used position, length, or angle as specifiers. However, graphs that used area or volume to represent quantitative values were associated with consistently worse performance than found with other formats.

Attention↗